transforming-growth-factor-beta and Psoriasis

GDF11 (Growth differentiation factor 11) is a newly discovered member of family of transforming growth factors-β. Its crucial role was confirmed in physiology, i.e. embryogenesis due to its involvement in bone formation, skeletogenesis and it is essential to stating skeletal pattern. GDF11 is described as a rejuvenating and anti-aging molecule, that could even restore functions. Beside embryogenesis, GDF11 participates in the process of inflammation and carcinogenesis. An anti-inflammatory effect of GDF11 was found in experimental colitis, psoriasis and arthritis. Current data regarding liver fibrosis and renal injury indicate that GDF11 may act as pro-inflammatory agent. In this review, we describe its involvement in regulation of acute and chronic inflammatory disorders.

Topics: Bone Morphogenetic Proteins; Growth Differentiation Factors; Humans; Inflammation; Osteogenesis; Psoriasis; Transforming Growth Factor beta

Ubiquitination is an important post-translational modification that regulates a myriad of biological processes such as inflammation, immune response, cell differentiation and proliferation. During the last decade, progress in proteomics contributed to the identification of new E3 ligases and their substrates. Hence, deregulated ubiquitination events are found to be involved in several inflammatory disorders, exemplifying by systemic lupus erythematosus (SLE), type 1 diabetes, rheumatoid arthritis (RA) and psoriasis. Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and differentiation. Through regulation of key transcriptional factors or signaling members, ubiquitination is viewed as a key regulator in psoriasis. Thus, targeting ubiquitination pathway holds potential for the treatment of psoriasis. Herein, we summarize the current understanding of ubiquitination in psoriasis, and discuss the prospects for targeting ubiquitination in the treatment of psoriasis.

Topics: Forkhead Transcription Factors; Humans; NF-kappa B; Nuclear Receptor Subfamily 1, Group F, Member 3; Proteasome Endopeptidase Complex; Psoriasis; Signal Transduction; Transforming Growth Factor beta; Ubiquitination

The present review describes in detail the existent data regarding feedback loops between miRNAs and cytokines or growth factors in the psoriatic inflammation. We have chosen to describe the roles of miR-31, miR-21, miR-146a, miR-155, miR-197 and miR-99a in this process. This choice derives from the fact that among around 250 miRNAs being altered in the psoriatic lesion, the comprehensive functional role was described only in those detailed above. In addition, considering the molecular targets and the pathways, which may possibly be regulated by those miRNAs, it seems that they may be chosen as preferred targets for the therapy of psoriasis.

Topics: Cytokines; Feedback, Physiological; Humans; Intercellular Signaling Peptides and Proteins; Interferon-gamma; MicroRNAs; NF-kappa B; Psoriasis; Receptor, IGF Type 1; Receptors, Interleukin; Receptors, Interleukin-17; Receptors, Somatomedin; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Psoriasis is a chronic immune-mediated inflammatory skin disease with both genetic and environmental factors contributing to its pathogenesis. Transforming Growth Factor beta (TGFbeta) is a member of a large family of pleiotropic cytokines with three different isoforms (TGFbeta1,2,3). Smads are a family of eight-related proteins that function as intracellular signaling intermediates for TGFbeta once the latter is bound to its receptors (TGFbRI, II and III). The involvement of Smads in TGFbeta signaling has been studied intensively in the skin in the process of wound healing. Few studies, and with controversial results, have investigated at the immunohistochemical and molecular level the role of TGFbeta/Smads signaling in psoriasis.

Topics: Humans; Psoriasis; Smad Proteins; Transforming Growth Factor beta

Deregulation of transforming growth factor-beta (TGFbeta) signaling has been reported in human psoriasis. Our recent study using a keratin 5 promoter (K5.TGFbeta1(wt)) showed that transgenic mice expressing wild-type TGFbeta1 in the epidermis developed severe skin inflammation. Additional experimental data further support a direct role for TGFbeta1 overexpression in skin inflammation. First, we temporally induced TGFbeta1 expression in keratinocytes in our gene-switch TGFbeta1(wt) transgenic mice and found inflammation severity correlated with TGFbeta1(wt) transgene expression. Second, deletion of T cells in K5.TGFbeta1(wt) mice significantly delayed skin inflammation and associated epidermal hyperplasia/hyperkeratosis. Third, therapeutic approaches effective for human psoriasis, that is, Etanercept and Rosiglitazone, are effective in alleviating the symptoms observed in K5.TGFbeta1(wt) mice. Future studies will analyze specific mechanisms and identify key factors in TGFbeta1-induced skin inflammation. Our mouse models will provide a useful tool for understanding the molecular mechanisms of inflammatory skin disorders in which TGFbeta1 is overexpressed.

Topics: Animals; Epidermis; Humans; Immune System; Inflammation; Keratinocytes; Mice; Mice, Transgenic; Psoriasis; Rosiglitazone; Signal Transduction; Skin; Skin Physiological Phenomena; Thiazolidinediones; Transforming Growth Factor beta; Transgenes

We have previously postulated that as well as T-helper (Th) 1 and Th17 cells, the transforming growth factor (TGF)-beta/fibronectin (FN)/alpha5beta1 pathway is central to psoriasis pathogenesis. EDA+ FN refers to an alternatively spliced isoform of FN with an additional domain known as extra domain A. EDA+ FN has two important properties pertinent to psoriasis lesions: it stimulates keratinocyte hyperproliferation, and, through stimulation of Toll-like receptor (TLR) 4, stimulates production of proinflammatory cytokines. EDA+ FN production induced by TGF-beta stimulation can be maintained in psoriasis lesions via two main feedback loops. Firstly, EDA+ FN stimulates proliferation of keratinocytes, which, in an autocrine fashion, will release more EDA+ FN. Secondly, EDA+ FN stimulates TLR4 expressed by antigen-presenting cells resulting in the production of proinflammatory cytokines such as tumour necrosis factor-alpha, interleukin (IL)-1, IL-6 and IL-12. The resultant promotion of cutaneous inflammation results in the recruitment of Th1 cells, which also produce EDA+ FN. We propose that these 'FN loops' contribute to the maintenance and progression of psoriatic lesions. Finally, although the association between psoriasis and heart/thrombotic disease remains unclear one plausible link may be the promotion of atherosclerosis and thrombotic heart disease by EDA+ FN.

Topics: Cell Proliferation; Cells, Cultured; Fibronectins; Humans; Keratinocytes; Protein Isoforms; Psoriasis; Toll-Like Receptor 4; Transforming Growth Factor beta

We have previously postulated that surviving invasive streptococcal infections may have been a factor in psoriasis becoming a common skin disease in some parts of the world. Many of the candidate genes linked to psoriasis are associated with the acquired or innate immune system, which are also important in host defence to invasive streptococcal infections. High rates of positive streptococcal throat swabs among patients with chronic plaque psoriasis suggest that they are efficient at internalizing/carrying beta-haemolytic streptococci. Internalization of streptococci in the throat is dependent upon the transforming growth factor (TGF)-beta/fibronectin/alpha 5 beta 1 integrin pathway. The immune cell Th17 and its related cytokine network are important in mucosal defence, being very effective against extracellular microbes but having little effect on intracellular organisms. The TGF-beta/fibronectin/alpha 5 beta 1 integrin pathway and the Th17 cell network also appear to be operative in psoriasis, animal models of both TGF-beta and alpha 5 beta 1 cutaneous overexpression being associated with characteristic psoriasis lesions. We postulate that some of the genotypic/phenotypic changes in different immunological pathways in psoriasis, including the acquired T-cell response, the innate immune response, the TGF-beta/fibronectin/alpha 5 beta 1 integrin pathway and the Th17 cell system, confer protection against mortality during epidemics of invasive streptococcal infections, heightened efficiency in internalizing and allowing carriage of streptococci as well as predisposition to the development of psoriasis.

Topics: Disease Outbreaks; Humans; Psoriasis; Selection, Genetic; Streptococcal Infections; Th1 Cells; Transforming Growth Factor beta

The beta 2 integrin family (CD11/CD18) of leukocyte adhesion molecules plays a key role in inflammation. Absence of the common chain (CD18) leads to leukocyte adhesion deficiency-1 (LAD1) in humans. We here summarize data of two genetically defined mice models of beta 2 integrin deficiency, one with a CD18 null mutation (CD18-/-), and the other one with a hypomorphic CD18 mutation (CD18hypo). Firstly, we focus on the underlying mechanism of a severely impaired wound healing in CD18-/- mice, outlining a scenario in which a defective extravasation and phagocytosis of CD18-/- neutrophils results in delayed myofibroblast-dependent wound contraction owing to a deficient transforming growth factor-beta 1 release. Based on this, we have identified a potential therapy that fully rescued the impaired wound healing in CD18-/- mice. Secondly, we expand on a CD18hyp0 PL/J mouse model closely resembling human psoriasis. Apart from common clinical and pathophysiological features, this psoriasiform dermatitis also depends on the presence of activated CD4+ T cells. We here recapitulate the influence of a reduced CD18 gene expression on T-cell function, also with regard to CD18 gene-dose effects, and its contribution to the pathogenesis of this disease. Taken together, these unique features make this model a valuable tool for investigations into the pathogenesis of human psoriasis--including its polygenic base--and future preclinical studies.

Topics: Animals; CD18 Antigens; Cell Differentiation; Fibroblasts; Humans; Inflammation; Mice; Psoriasis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Following injury, skin establishes a balance between too little inflammation increasing risk of infection, and excessive inflammation contributing to delayed wound healing and scarring. Mounting evidence indicates both initiation and termination of inflammation involve active mechanisms. Not only does inflammation itself seem to be a paradox because inflammatory responses are both essential and potentially detrimental, but one chronic inflammatory skin disease (e.g. psoriasis) presents additional paradoxes. While plaques share several factors with wound healing, two understudied and puzzling aspects include why do not inflamed plaques more frequently transform?; and why do not plaques result in scarring? To get at these questions, we review responses involved in wound repair. Oral mucosa was probed because, like fetal skin, wound repair is characterized by its rapidity, low inflammation, and scarless resolution. Active roles for macrophages as both initiators and terminators of inflammation are highlighted. Therapeutic implications are discussed regarding psoriasis and pyoderma gangrenosum. Based on biochemical and immunohistochemical considerations linking psoriatic plaques to hard palate, a novel metaplastic model is presented. We hypothesize saliva and chronic trauma contribute to a constitutive epithelial program where keratinocyte proliferation is more intense prior to differentiation, accompanied by keratin 16 expression in hard palate, thereby resembling plaques. Rather than viewing psoriasis as a nonspecific response to inflammation, we postulate a metaplastic switch by which prepsoriatic skin is converted to a distinct adult tissue type resembling hard palate. In summary, many lessons can be learned by focusing on complex processes involved in regulation of inflammation, tissue repair, and remodeling.

Topics: Fibrosis; Humans; Inflammation; Macrophages; Psoriasis; Skin; Skin Neoplasms; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

Previously, we have shown that transforming growth factor beta 1 (TGFbeta1) overexpression in suprabasal epidermis suppresses skin carcinogenesis at early stages, but promotes tumor invasion at later stages. To elucidate the role of TGFbeta1 overexpression in naturally occurring human squamous cell carcinomas (SCC), we screened TGFbeta1 expression patterns in human skin SCC samples and found that TGFbeta1 was overexpressed with two distinct patterns: either predominantly in suprabasal layers or throughout tumor epithelia including basal proliferative cells. To determine the effect of TGFbeta1 overexpression in basal keratinocytes, we generated transgenic mice expressing wild-type TGFbeta1 in basal keratinocytes and hair follicles using the K5 promoter (K5.TGFbeta1(wt)). Surprisingly, these mice developed a severe inflammatory skin disorder. Inflammation was also observed in head and neck tissue when TGFbeta1 transgene expression was inducibly expressed in head and neck epithelia in our gene-switch-TGFbeta1 transgenic mice. Given the importance of inflammation in cancer development, our data suggest that TGFbeta1-induced inflammation may override its tumor-suppressive effect even at early stages of skin carcinogenesis. This notion is further suggested by our recent study that Smad3 knockout mice were resistant to skin chemical carcinogenesis at least in part via abrogation of endogenous TGFbeta1-induced inflammation.

Topics: Animals; Dermatitis; Humans; Psoriasis; Signal Transduction; Skin Neoplasms; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: CD8-Positive T-Lymphocytes; Humans; Immunoglobulin A; Psoriasis; Spondylitis, Ankylosing; Transforming Growth Factor beta

Psoriasis is characterized by the hyperproliferation of keratinocytes in the epidermis and the accumulation of activated CD4+ T lymphocytes in the upper dermis. We have recently rested the hypothesis that the abnormal endothelial proliferation in the dermal papillae of psoriatic lesions may be mechanistically linked to the expression of endothelial ligands capable of promoting lymphocytes binding and extravasation. The results indicated that specialized endothelial cells lining the post-capillary venules of psoriatic lesions are capable of promoting the selective adherence of human CD4+ T cells and its memory subset. In contrast, B cells, CD8+ T cells, and CD45RA+ T cells are deficient in their capacities to bind. The adhesion process is energy and calcium dependent and involves tissue-specific lymphocyte receptors, with LFA-1 molecules playing an accessory role. We concluded that transformation of the dermal endothelium into a lymphocyte-receptive phenotype by defined growth factors or cytokines may represent a positive feedback mechanism promoting lymphocyte migration into the diseased sites.

Topics: Cell Adhesion; Cell Movement; Endothelium, Vascular; Humans; Integrin beta1; Leukocyte Common Antigens; Psoriasis; Skin; T-Lymphocytes; Transforming Growth Factor beta

Because molecular memories of past inflammatory events can persist in epidermal cells, we evaluated the long-term epidermal protein expression landscapes after dermal regeneration and in psoriatic inflammation. We first characterized the effects of two dermal regeneration strategies on transplants of indicator split-thickness skin grafts (STSGs) in ten adult patients with deep burns covering more than 20% of their body surface area. After fascial excision, three adjacent areas within the wound were randomized to receive a permanent dermal matrix, a temporary granulation-tissue-inducing dressing or no dermal component as control. Control areas were covered with STSG immediately, and treated areas after two-weeks of dermis formation. Epidermis-dermis-targeted proteomics of one-year-follow-up samples were performed for protein expression profiling. Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Given the dermal inflammatory component found in our dermal regeneration samples as well as in early psoriatic lesions, we hypothesized that DNAH10 protein expression also would be affected in psoriatic skin samples. We discovered increased DNAH10 expression in inflammatory lesions when compared to unaffected skin. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. This study (ISRCTN14499986) was funded by the Finnish Ministry of Defense and by government subsidies for medical research.

Topics: Adult; Burns; Cell Proliferation; Dermis; Dyneins; Epidermis; Female; Humans; Immunohistochemistry; Inflammation; Keratinocytes; Male; Middle Aged; Psoriasis; Regeneration; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing; Young Adult

Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system. Pro-inflammatory cytokine secretion drives a T helper 17 response and an imbalance of regulatory T cells. We hypothesized that MSC adoptive cellular therapy could immunomodulate and suppress the effector T cell hyperactivation that underlies the disease. We used the imiquimod-induced psoriasis-like skin inflammation model to study the therapeutic potential of bone marrow and adipose tissue-derived MSC in vivo. We compared the secretome and the in vivo therapeutic potential of MSC with and without cytokine pre-challenge ("licensing"). The infusion of both unlicensed and licensed MSC accelerated the healing of psoriatic lesions, and reduced epidermal thickness and CD3

Topics: Animals; Cytokines; Dermatitis; Inflammation; Interleukin-17; Interleukin-6; Mesenchymal Stem Cells; Mice; Psoriasis; Skin; Transforming Growth Factor beta

Alterations in extracellular matrix (ECM) components that modulate inflammatory cell behavior have been shown to serve as early starters for multifactorial diseases such as fibrosis and cancer. Here, we demonstrated that loss of the ECM glycoprotein EMILIN-1 alters the inflammatory context in skin during IMQ-induced psoriasis, a disease characterized by a prominent inflammatory infiltrate and alteration of vessels that appear dilated and tortuous. Abrogation of EMILIN-1 expression or expression of the EMILIN-1 mutant E933A impairs macrophage polarization and leads to imbalanced tissue homeostasis. We found that EMILIN-1 deficiency is associated with dilated lymphatic vessels, increased macrophage recruitment and psoriasis severity. Importantly, the null or mutant EMILIN-1 background was characterized by the induction of a myofibroblast phenotype, which in turn drove macrophages towards the M1 phenotype. By using the transgenic mouse model carrying the E933A mutation in the gC1q domain of EMILIN-1, which abolishes the interaction with α4- and α9-integrins, we demonstrated that the observed changes in TGFβ signaling were due to both the EMI and gC1q domains of EMILIN-1. gC1q may exert multiple functions in psoriasis, in the context of a final, more consistent inflammatory condition by controlling skin homeostasis via interaction with both keratinocytes and fibroblasts, influencing non-canonical TGFβ signaling, and likely acting on lymphatic vessel structure and function. The analyses of human psoriatic lesions, in which lower levels of EMILIN-1 were present with a very rare association with lymphatic vessels, support the multifaceted role of this ECM component in the skin inflammatory scenario.

Topics: Animals; Humans; Integrin alpha4beta1; Membrane Glycoproteins; Mice; Mice, Transgenic; Psoriasis; Transforming Growth Factor beta

To compare the phenotype and adipogenic and osteogenic differentiation capacities of adipose-derived mesenchymal stem cells (AMSCs) isolated from patients with psoriasis vulgaris and healthy donors, and to explore the effects of astragaloside IV, a Traditional Chinese Medicine, on the immunoregulatory function of AMSCs.. AMSCs were isolated from human adipose tissue and cultured for three generations in vitro. Cell phenotype and cell cycle analysis were performed by flow cytometry. Adipogenic and osteogenic differentiation of AMSCs was examined by lipid (oil red O) and alkaline phosphatase staining, respectively. Expression of inflammatory mediators was examined by real-time quantitative polymerase chain reaction analysis, and proliferation was quantified using the cell counting kit-8 assay.. Expression of CD29, CD44, and CD73 was higher in AMSCs from healthy donors than psoriasis patients, while the reverse was true for expression of CD45, CD31, and HLA-DR. AMSCs from psoriasis patients had a greater ability to undergo adipogenic differentiation than cells from healthy donors, whereas there was no significant difference in osteogenic differentiation between AMSCs from the two sources. Compared with AMSCs from healthy donors, psoriasis patient-derived AMSCs expressed lower levels of the anti-inflammatory cytokines interleukin-10 and trans-forming growth factor-β (TGF-β) and the immune checkpoint ligand programmed cell death 1 ligand 1 (PD-L1) (P < 0.05) and higher levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Incubation of AMSCs from psoriasis patients with astragaloside IV had no significant effect on pro-liferation but increased the expression of TGF-β and PD-L1 and decreased the expression of IFN-γ and TNF-α.. AMSCs from patients with psoriasis vulgaris display abnormal proliferation and adipogenesis and an enhanced pro-inflammatory phenotype. These defects were normalized by treatment with astragaloside IV, suggesting that this Traditional Chinese Medicine may be useful for restoring the immunoregulatory function of AMSCs and immune homeostasis in patients with psoriasis vulgaris.

Topics: Adipose Tissue; B7-H1 Antigen; Cell Differentiation; Cells, Cultured; Humans; Mesenchymal Stem Cells; Osteogenesis; Psoriasis; Saponins; Transforming Growth Factor beta; Triterpenes; Tumor Necrosis Factor-alpha

Psoriasis (PsO) is a systemic autoimmune disease. Many pro-inflammatory and anti-inflammatory biomarkers have been associated with the pathogenetic process of psoriasis. IL-35 act as an anti-inflammatory cytokine through downregulation of TH-17 cell development and cytokine production. So, IL-35 might be utilized as potential future therapeutic agent for psoriasis.. To investigate the association between inflammatory (IL-17, TNF-α, IFN-γ) and anti-inflammatory cytokines (IL-35, TGF-β) in psoriasis patients.. A case-control study enrolled two groups: (Group I: 40 patients with psoriasis) and (Group II: 40 healthy age and sex-matched subjects). Full history was taken from all cases along with full dermatologic examination. The assessment of psoriasis severity was conducted by using PASI score. Assessment of inflammatory (IL-17, TNF-α, IFN-γ) and anti-inflammatory cytokines (IL-35, TGF-β) was performed by using ELISA technique.. There was a statistically significant increase of mean level of TNF-α, IL-17, and IFN-γ among psoriasis cases in comparison with controls. The mean level of TGF-β and IL-35 was statistically significantly reduced among the psoriasis cases in comparison with controls. TNF-α, IL-17, and IFN-γ showed a significant strong positive association in between and statistically significant strong negative relationship with IL-35 and TGF-β.. IL-35 has a significant role in the pathogenetic process of PsO, and it serves as a potential future therapeutic agent for psoriasis. The current results could be used as a clue for the utilization of inflammatory (IL-17, TNF-α, IFN-γ) versus anti-inflammatory cytokines (IL-35, TGF-β) in psoriasis patients as a diagnostic biomarker for severity of cases with psoriasis.

Topics: Anti-Inflammatory Agents; Case-Control Studies; Cytokines; Humans; Interleukin-17; Psoriasis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Previous studies have not completely elucidated the role of the histaminergic system in the pathogenesis of psoriasis. This study aimed to evaluate the effects of adalimumab and cyclosporine A on the expression of histaminergic system-related genes and miRNAs regulating these genes in bacterial lipopolysaccharide A (LPS)-stimulated human keratinocyte (HaCaT) cells. HaCaT cells were treated with 1 µg/mL LPS for 8 h, followed by treatment with 8 µg/mL adalimumab or 100 ng/mL cyclosporine A for 2, 8, or 24 h. Untreated cells served as controls. The cells were subjected to ribonucleic acid (RNA) extraction and microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay analyses. Statistical analysis was performed using the Statistica 13.0 PL (StatSoft, Cracow, Poland) and the Transcriptome Analysis Console programs (Affymetrix, Santa Clara, CA, USA) (

Topics: Adalimumab; Adult; Cyclosporine; gamma-Aminobutyric Acid; HaCaT Cells; Histamine N-Methyltransferase; Humans; Lipopolysaccharides; Matrix Metalloproteinase 2; MicroRNAs; Phosphatidylinositol 3-Kinases; Polycomb Repressive Complex 1; Psoriasis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

An interplay between immune cells and resident skin and joint stromal cells is implicated in psoriatic arthritis (PsA), yet the mechanisms remain elusive with a paucity of molecular biomarkers for activity and response. Combined transcriptomic and immunophenotypic analysis of whole blood and skin fibroblasts could provide further insights.. Whole blood RNA-seq was performed longitudinally in 30 subjects with PsA at the beginning, one and six months after treatment, with response defined at six months. As control groups, 10 healthy individuals and 10 subjects with rheumatoid arthritis (RA) were recruited combined with public datasets from patients with psoriasis (PsO) and systemic lupus erythematous (SLE). Differential expression analysis and weighted gene co-expression network analysis were performed to identify gene expression signatures, while deconvolution and flow cytometry to characterize the peripheral blood immune cell profile. In a subset of affected and healthy individuals, RNA-seq of skin fibroblasts was performed and subjected to CellChat analysis to identify the blood-skin fibroblast interaction network.. PsA demonstrated a distinct "activity" gene signature in the peripheral blood dominated by TNF- and IFN-driven inflammation, deregulated cholesterol and fatty acid metabolism and expansion of pro-inflammatory non-classical monocytes. Comparison with the blood transcriptome of RA, PsO, and SLE revealed a ". Transcriptome analysis of peripheral blood and skin fibroblasts in PsA reveals a distinct disease activity signature and supports the involvement of skin fibroblasts through their activation and interaction with circulating immune cells. Aberrant TGFβ signaling and persistently increased non-classical monocytes characterize treatment-resistant PsA, with pro-inflammatory pathways related to platelet activation and Hippo signaling predicting early response to treatment.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Biomarkers; Fatty Acids; Fibroblasts; Gene Expression Profiling; Humans; Lupus Erythematosus, Systemic; Psoriasis; Semaphorins; Transcriptome; Transforming Growth Factor beta

Regulatory T cells (Tregs) are crucial in maintaining T cell homeostasis and preventing autoimmune responses. Deficiencies in the suppressive function of Tregs contribute to the pathogenesis of various autoimmune diseases, such as psoriasis. However, whether IL-17A upregulation in psoriatic patients contributes to Treg dysfunction is unknown.. To explore the effect and underlying mechanism of IL-17A on the suppressive function of Tregs and to evaluate the restoration of the suppressive function of Tregs in psoriasis during anti-IL-17A (secukinumab) treatment.. In vitro suppression assays were performed with or without the addition of IL-17A to the coculture system. The release of inhibitory cytokines, including IL-10 and TGF-β, was assessed by qRT-PCR and flow cytometry. RNA-sequencing was conducted to characterize the cellular responses of Tregs. IL-17A signaling activation was analyzed by flow cytometry and immunofluorescence. Blood samples were collected from three psoriasis patients before and after secukinumab treatment.. IL-17A blocked the suppressive function of Tregs, possibly by inhibiting the release of TGF-β and promoting the production of IFN-γ. Moreover, IL-17A activated the NF-κB signaling pathway in Tregs. Inhibition of the NF-κB pathway blocked IL-17A-induced upregulation of IFN-γ without affecting the secretion of TGF-β by Tregs. Clinical treatment in psoriasis with secukinumab restored the suppressive function and increased production of TGF-β in Tregs of psoriasis.. Our study implies a crucial role of IL-17A in mediating the dysfunction of the Treg suppressive function in psoriasis. Secukinumab, which neutralizes IL-17A signaling, restored the suppressive function of Tregs to exert its antipsoriatic effect.

Topics: Adult; Antibodies, Monoclonal, Humanized; Coculture Techniques; Dermatologic Agents; Female; Healthy Volunteers; Humans; Injections, Subcutaneous; Interferon-gamma; Interleukin-17; Male; Middle Aged; Nitriles; Phosphorylation; Psoriasis; Recombinant Proteins; RNA-Seq; Signal Transduction; Sulfones; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Treatment Outcome

The transforming growth factor β (TGFβ) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFβ and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease.. Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGFβ mAb.. Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGFβ activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls).. These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Arthritis, Experimental; Arthritis, Psoriatic; CD4-Positive T-Lymphocytes; Cell Differentiation; Collagen Type II; Disease Models, Animal; Imiquimod; Interleukin-17; Interleukin-2; Mannans; Membrane Proteins; Mice; Mice, Knockout; Psoriasis; Saccharomyces cerevisiae; Skin; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Psoriasis course involves increased secretion of pro-inflammatory cytokines, among others, a beta transforming growth factor (TGFβs) and its receptors. Cyclosporine A (CsA), an immunosuppressive medicine with the molecular mechanism of operation connected with the properties of cell cycle suppression, is often used in the treatment of severe forms of psoriasis. The efficacy of therapy is assessed based on the disease clinical progression indexes - Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Dermatology Life Quality Index (DLQI). The aim of the study was the evaluation of the efficacy of the CsA treatment of patients with psoriasis vulgaris, based on the clinical parameters and an assessment of the expression profiles of TGFβs and TGFβRs, depending on the concurrent diabetes and metabolic syndrome.. The group under study composed of 32 patients (15 with the metabolic syndrome, seven with diabetes) treated with CsA for 84 days. The molecular analysis included extraction of RNA, assessment of TGβF1-3, TGFβRI-III gene expression with the use of the RTqPCR method. The clinical assessment of the effects of this pharmacotherapy involved evaluation of the parameters: PASI, BSA, DLQI before therapy commencement, on the 42nd and 84th days of therapy.. A statistically significant change in the transcription activity of TGFβ1 in patients with and without diabetes (P = 0.018) and patients with and without metabolic syndrome (P = 0.023) was shown that on the 84th day of therapy.. TGFb1 may be claimed as the supplementary molecular marker to evaluate the efficacy of CsA therapy. It seems that systemic diseases have an effect on the efficacy of the applied pharmacotherapy and the course of psoriasis.

Topics: Cyclosporine; Diabetes Complications; Female; Gene Expression; Humans; Immunosuppressive Agents; Male; Metabolic Syndrome; Proteoglycans; Psoriasis; Quality of Life; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Severity of Illness Index; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Treatment Outcome

Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44

Topics: Cells, Cultured; Humans; Interleukin-17; Interleukin-1beta; Interleukin-23 Subunit p19; Interleukin-4; Lymphocytes; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-kit; Psoriasis; Receptors, CCR10; Skin; Transforming Growth Factor beta

Bai Xuan Xia Ta Re Pian (BXXTR) is a traditional Uighur medicine ancient prescription in China widely used in the treatment of psoriasis, presenting a high curative rate and few side effects. Given that the active constituents and action mechanism still remain unclear, the aim of this study is to explore the potential active constituents and mechanism of antipsoriasis of BXXTR. Psoriasis-like lesions model in BALB/c mice was induced by Imiquimod (IMQ), including five treatment groups: control group, IMQ-treated group, IMQ-ACITRETIN group (Positive control group), IMQ-BXXTR low dose group, IMQ-BXXTR medium dose group and IMQ-BXXTR high dose group. The Psoriasis Area and Severity Index (PASI) score, skin and ear thickness, and histologic section were collected. The differentially expressed genes were determined by using RNAseq technology and the relevant pathways were analyzed by KEGG database. The ELISA kit and western blot assays were used to detect the related protein expression levels. In addition, the chemical constituents of BXXTR were determined by UPLC-TOF-MS analysis and the potential active constituents were predicted by SEA DOCK and Gene Ontology (GO). The data demonstrated that BXXTR significantly alleviated IMQ-induced psoriasis. RNA-seq analysis showed that BXXTR induced the expression levels of 31 genes; the KEGG analysis suggested that BXXTR could significantly change IL-17-related inflammatory pathways. The ELISA kit confirmed that the expression level of IL-17A protein was significantly reduced. 75 compounds of BXXTR were determined by UPLC-TOF-MS analysis, 11 of 75 compounds were identified as potential active compounds by similarity ensemble approach docking (SEA DOCK) and Gene Ontology (GO). BXXTR reduced the severity of skin lesions by inhibiting IL-17-related inflammatory pathways. The results indicated that BXXTR could suppress psoriasis inflammation by multiple-constituents-regulated multiple targets synergistically. Collectively, this study could provide important guidance for the elucidation of the active constituents and action mechanism of BXXTR for the treatment of psoriasis.

Topics: Aminoquinolines; Animals; Cell Proliferation; Dermatologic Agents; Disease Models, Animal; Drugs, Chinese Herbal; Gene Expression Regulation; Humans; Imiquimod; Interleukin-17; Interleukin-18; Interleukin-23; Keratinocytes; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Psoriasis; Severity of Illness Index; Signal Transduction; Skin; Toll-Like Receptor 8; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Keratin 17 (K17) is strongly expressed in psoriatic lesions but not healthy skin, and plays a crucial role in disease pathogenesis. The mechanism of aberrant K17 expression in psoriasis has not been fully elucidated. MicroRNAs are short, single-stranded, noncoding RNAs that play important roles in regulating gene expression. Psoriasis exhibits a specific microRNA expression profile distinct from that of healthy skin. In this study, we showed that miR-486-3p was markedly reduced in psoriatic epidermis and negatively correlated with the psoriasis area and severity index score. Its expression repressed K17 protein expression and decreased proliferation in a keratinocyte cell line overexpressing K17 (LV K17) compared with controls. Our data indicated that miR-486-3p was regulated by a transforming growth factor-β (TGFβ)/SMAD pathway and possibly mediated the downregulation of K17 protein in TGFβ-treated keratinocytes. Finally, the decreased expression of TGFβ receptor I in psoriatic epidermis inactivated the TGFβ/SMAD pathway, leading to K17 overexpression and cell proliferation. Collectively, our findings demonstrated that a TGFβ/SMAD/miR-486-3p signaling axis in keratinocytes regulated K17 expression and cell proliferation. We conclude that the loss of miR-486-3p in psoriatic epidermis leads to K17 protein overexpression and contributes to the pathogenesis of psoriasis. Overexpression of miR-486-3p may therefore be a therapeutic option for psoriasis.

Topics: Blotting, Western; Cell Line; Cell Proliferation; Gene Expression Regulation; Humans; Keratin-17; Keratinocytes; MicroRNAs; Psoriasis; Real-Time Polymerase Chain Reaction; RNA; Signal Transduction; Skin; Smad Proteins; Transforming Growth Factor beta

Topics: Adult; Case-Control Studies; CD4-Positive T-Lymphocytes; Cytokines; Female; Humans; Male; MicroRNAs; Nuclear Receptor Subfamily 1, Group F, Member 3; Psoriasis; RNA, Messenger; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Up-Regulation

Topics: Cell Proliferation; Humans; Keratinocytes; Psoriasis; Smad7 Protein; Transforming Growth Factor beta; Transforming Growth Factors

Data indicate that in psoriasis, abnormalities are already present in nonlesional skin. Transforming growth factor-β and keratinocyte growth factor (KGF), together with fibronectin and α5β1 integrin, were suggested to play a crucial role in the pathogenesis of psoriasis by influencing inflammation and keratinocyte hyperproliferation.. To investigate the expression of KGF, fibroblast growth factor receptor (FGFR)2, fibronectin (FN) and extra domain A (EDA)-positive FN in healthy and nonlesional psoriatic skin, and to study the effect of KGF on the regulation of FN and EDA(+) FN production by fibroblasts.. Healthy, nonlesional psoriatic skin and lesional psoriatic skin were immunostained for α5 integrin, KGF, FGFR2, EDA(+) FN and signal transducer and activator of transcription (STAT)1. KGF-treated cell cultures were analysed for FN and EDA(+) FN mRNA and protein by real-time reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. The major downstream signalling of KGF was investigated by blocking experiments using inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK1), AKT1/2, STAT1 and STAT3.. The expression of α5 integrin, EDA(+) FN, KGF and its receptor FGFR2 is elevated in psoriatic nonlesional skin compared with healthy skin. KGF mildly induced EDA(+) FN, but not FN expression in healthy fibroblasts through MAPK signalling. Fibroblasts express the FGFR2-IIIc splice variant. STAT1 negatively regulates both FN and EDA(+) FN expression in healthy fibroblasts, and this regulation is compromised in fibroblasts derived from nonlesional psoriatic dermis. We detected active STAT1 in healthy and lesional skin, similarly to a previous report. However, in the nonlesional skin STAT1 activation was absent in tissues far away from lesions.. The production of FN and EDA(+) FN by fibroblasts and the signalling of STAT1 are abnormally regulated in psoriatic nonlesional skin.

Topics: Adolescent; Adult; Case-Control Studies; Cells, Cultured; Fibroblast Growth Factor 7; Fibroblasts; Fibronectins; Healthy Volunteers; Humans; Keratinocytes; MAP Kinase Signaling System; Melanocytes; Middle Aged; Psoriasis; Receptor, Fibroblast Growth Factor, Type 2; STAT1 Transcription Factor; STAT3 Transcription Factor; Transforming Growth Factor beta; Young Adult

Transforming growth factor (TGF)-β signaling plays an important role in the pathogenesis of psoriasis. CD109, a novel TGF-β co-receptor, which inhibits TGF-β signaling by enhancing Smad7-dependent degradation of TGF-β type I receptor (TGF-β RI), is abnormally expressed in psoriasis. To date, the expression of Smad7 and the correlation between CD109 and Smad7 expression in psoriasis have not been fully elucidated. This study was designed to investigate the expression and the correlation of CD109 and TGF-β signaling associated proteins in psoriasis and their roles in the pathogenesis of psoriasis. Thirty-two psoriasis specimens were subjected to immunohistochemical staining for CD109, Smad7, TGF-β RI and Ki67. Ten normal skin (NS) specimens served as controls. The positive expression rate (% positive cells) of Smad7 and Ki67 in psoriasis was significantly higher than in NS (62.6%±19.9% vs. 17.2%±4.4%, and 50.7%±14.3% vs. 19.5%±3.2%, respectively, P<0.001), and the expression levels of CD109 and TGF-β RI were reduced significantly in psoriasis as compared with NS (8.1%±6.7% vs. 35.8%±6.7% and 27.3%±3.4% vs. 3.0%±3.4%, respectively, P<0.001). There were significantly negative correlations between CD109 and Smad7 (r=-0.831, P<0.01). These findings indicated that CD109 might play a certain role in the pathogenesis of psoriasis. Lower expression of CD109 and TGF-β RI was highly correlated with higher expression of Smad7 and Ki67, suggesting that CD109 may induce the pathogenesis of psoriasis through Smad7-mediated degradation of TGF-β RI, and lead to the termination of TGF-β signaling.

Topics: Adolescent; Adult; Antigens, CD; Case-Control Studies; Down-Regulation; Female; GPI-Linked Proteins; Humans; Male; Middle Aged; Neoplasm Proteins; Psoriasis; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta; Up-Regulation

T helper type 9 (TH9) cells can mediate tumor immunity and participate in autoimmune and allergic inflammation in mice, but little is known about the TH9 cells that develop in vivo in humans. We isolated T cells from human blood and tissues and found that most memory TH9 cells were skin-tropic or skin-resident. Human TH9 cells coexpressed tumor necrosis factor-α and granzyme B and lacked coproduction of TH1/TH2/TH17 cytokines, and many were specific for Candida albicans. Interleukin-9 (IL-9) production was transient and preceded the up-regulation of other inflammatory cytokines. Blocking studies demonstrated that IL-9 was required for maximal production of interferon-γ, IL-9, IL-13, and IL-17 by skin-tropic T cells. IL-9-producing T cells were increased in the skin lesions of psoriasis, suggesting that these cells may contribute to human inflammatory skin disease. Our results indicate that human TH9 cells are a discrete T cell subset, many are tropic for the skin, and although they may function normally to protect against extracellular pathogens, aberrant activation of these cells may contribute to inflammatory diseases of the skin.

Topics: Animals; Autocrine Communication; Candida albicans; Dermatitis, Atopic; Humans; Inflammation; Interleukin-2; Interleukin-9; Lymphocyte Activation; Mice; Paracrine Communication; Psoriasis; Skin; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta

Although regulatory T cells (Tregs) are affected in several autoimmune skin diseases, only two studies have been performed in patients with bullous pemphigoid (BP) with contrasting results.. To characterize Tregs and to determine the serum levels of regulatory cytokines in patients with BP.. In BP lesional skin, immunohistochemistry and confocal microscopy were performed for CD4(+) , CD25(+) , forkhead/winged helix transcription factor (FOXP3)(+) , transforming growth factor (TGF)-β(+) and interleukin (IL)-10(+) cells. In addition, the number of CD4(+) CD25(++) FOXP3(+) Tregs in peripheral blood was assessed by flow cytometry, and the levels of TGF-β and IL-10 were determined in serum samples by enzyme-linked immunosorbent assay before and after steroid therapy. Controls included patients with psoriasis, atopic dermatitis (AD) and healthy donors.. The frequency of FOXP3(+) cells was significantly reduced in skin lesions from patients with BP (P < 0.001) compared with psoriasis and AD. Moreover, the number of IL-10(+) cells was lower in BP than in psoriasis (P < 0.001) and AD (P = 0.002), while no differences were observed in the number of TGF-β(+) cells. CD4(+) CD25(++) FOXP3(+) Treg in the peripheral blood of patients with BP was significantly reduced compared with healthy controls (P < 0.001), and augmented significantly after steroid therapy (P = 0.001). Finally, TGF-β and IL-10 serum levels were similar in patients with BP compared with healthy controls. However, after therapy, BP patients showed significantly higher IL-10 serum levels than before therapy (P = 0.01).. These data suggest that the depletion of Tregs and of IL-10 in patients with BP may be an important factor in the pathogenesis of the disease.

Topics: Adult; Aged; Aged, 80 and over; CD4 Antigens; CD4 Lymphocyte Count; Dermatitis, Atopic; Female; Forkhead Transcription Factors; Humans; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Male; Middle Aged; Pemphigoid, Bullous; Psoriasis; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Young Adult

Psoriasis and atopic dermatitis (AD) are the most common chronic inflammatory skin diseases. Although both patient groups show strongly impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infections. The mechanisms underlying the distinct susceptibilities to these pathogenetic and often life-threatening infections are unknown. We show that antiviral proteins (AVPs) such as MX1, BST2, ISG15, and OAS2 were strongly elevated in psoriatic compared to AD lesions and healthy skin. Of 30 individually quantified cytokines in psoriatic lesions, interleukin-29 (IL-29) was the only mediator whose expression correlated with the AVP levels. IL-29 was absent in AD lesions, and neutralization of IL-29 in psoriatic skin reduced AVP expression. Accordingly, IL-29 raised AVP levels in isolated keratinocytes, epidermis models, and human skin explants, but did not influence antibacterial protein production. AVP induction correlated with increased antiviral defense of IL-29-treated keratinocytes. Furthermore, IL-29 elevated the expression of signaling elements, resulting in increased sensitivity of keratinocytes toward its own action. We identified T helper 17 (T(H)17) cells as IL-29 producers and demonstrated their ability to increase the antiviral competence of keratinocytes in an IL-29-dependent manner. Transforming growth factor-β and the activity of RORγt/RORα were most critical for the development of IL-29-producing T(H)17 cells. IL-29 secretion by these cells was dependent on NFAT and c-Jun N-terminal kinase and was inhibited by IL-4. These data suggest that T(H)17 cell-derived IL-29, which is absent in AD, mediates the robust antiviral state on psoriatic skin, and demonstrate a new function of T(H)17 cells.

Topics: Adult; Dermatitis, Atopic; Herpesvirus 1, Human; Humans; Interferon-gamma; Interferons; Interleukins; Keratinocytes; Psoriasis; Signal Transduction; Skin; Th17 Cells; Transforming Growth Factor beta

T-lymphocytes are believed to play an important role in the pathogenesis of discoid lupus erythematosus (DLE). However, the reasons that lead to loss of tolerance and to development of autoimmunity in DLE remain unclear. In the present paper, we investigated serum levels of the regulatory cytokines transforming growth factor (TGF)-β and interleukin (IL)-10 in 25 newly diagnosed patients with DLE, 15 with systemic lupus erythematosus (SLE), 10 with psoriasis, 10 with atopic dermatitis (AD) and 20 healthy controls (HC). TGF-β serum levels were significantly lower in patients with DLE compared with patients with psoriasis and HC, while no differences were found between DLE, SLE and AD (medians: DLE: 28.49 ng/ml; psoriasis: 42.77 ng/ml; HC: 43.71 ng/ml; DLE vs. psoriasis: p < 0.05; DLE vs. HC: p < 0.05). IL-10 concentrations were reduced in DLE serum samples with respect to SLE, psoriasis, AD and HC (medians: DLE: 46.42 pg/ml; SLE: 127.64 pg/ml; psoriasis: 109.3 pg/ml; AD: 76.3 pg/ml; HC: 114.71 pg/ml; DLE vs. SLE: p < 0.05; DLE vs. psoriasis: p < 0.05; DLE vs. AD: p < 0.05; DLE vs. HC: p < 0.05). The downregulation of TGF-β and IL-10 in DLE may lead to defective immune suppression and thus to the generation of the tissue injury that is found in lupus patients.

Topics: Adult; Case-Control Studies; Dermatitis, Atopic; Down-Regulation; Female; Humans; Interleukin-10; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Male; Middle Aged; Psoriasis; Transforming Growth Factor beta

Transforming growth factor (TGF)-β is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-β signalling has been reported in psoriasis, where despite increased expression of TGF-β, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-β signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-β signalling and TGF-β receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl-2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-β receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-β receptor downregulation and decrease in TGF-β signalling in psoriasis.

Topics: Antigens, CD; Cell Line; Cell Membrane; Cell Proliferation; Cell Survival; GPI-Linked Proteins; Humans; Keratinocytes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Psoriasis; Receptors, Transforming Growth Factor beta; Signal Transduction; STAT3 Transcription Factor; Transforming Growth Factor beta

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-beta1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10-producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.

Topics: Animals; Antigens, CD; Cell Separation; CTLA-4 Antigen; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; Forkhead Transcription Factors; Humans; Immunoassay; Immunohistochemistry; Interleukin-17; Interleukin-23; Methoxsalen; Mice; Mice, Transgenic; Photosensitizing Agents; Phototherapy; Psoriasis; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Ultraviolet Rays

Topics: Coronary Artery Disease; Ectodysplasins; Fibronectins; Humans; Psoriasis; Streptococcus; Transforming Growth Factor beta

Transforming growth factor beta (TGFbeta) has been suggested to be an effective inhibitor of the increased keratinocyte proliferation in psoriasis. Three TGFbeta isoforms are described (TGFbeta1, 2 and 3), signalling via a heteromeric receptor complex of TGFbetaRI and TGFbetaRII. Receptor binding activates SMAD2, 3 and 4, which translocate into the nucleus and regulate TGFbeta-responsive genes. SMAD6 and 7 proteins represent a negative feedback loop inhibiting the TGFbeta-SMAD signalling path-way. As TGFbeta1 overexpression inhibits keratinocyte proliferation, the aim of this study was to investigate with real-time RT-PCR the expression of TGFbeta1, 2 and 3, TGFbetaRI and TGFbetaRII and SMAD2, 3, 4, 6 and 7 in lesional and non-lesional psoriatic skin from 13 patients with chronic plaque-type psoriasis as compared to skin from 10 healthy subjects . The study data demonstrate significantly downregulated TGFbetaRI and SMAD2, 4 and 6 mRNA expression in lesional and non-lesional psoriatic skin. SMAD7 mRNA expression was significantly decreased in lesional psoriatic skin compared with both non-lesional psoriatic skin and healthy skin. A significant TGFbeta3 and TGFbetaRII mRNA upregulation exclusively in non-lesional psoriatic skin but no significant difference in the expression of TGFbeta1 and 2 was found. The results of this study suggest that the expression of TGFbeta isoforms, receptors and SMADs may be involved in the increased proliferation of keratinocytes in psoriatic skin.

Topics: Adult; Down-Regulation; Female; Humans; Male; Protein Serine-Threonine Kinases; Psoriasis; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad4 Protein; Smad6 Protein; Smad7 Protein; Transforming Growth Factor beta

Pustulosis palmaris et plantaris (PPP) is known to be a skin disease related to tonsillitis, because the pustulosis often become exacerbated during acute tonsillitis and disappears after tonsillectomy. However, etiology of PPP remains unclear. In this study, we investigated the activation of tonsillar T-cell from PPP patients. Furthermore, we analyzed expressions of cytotoxic T-lymphocyte antigen-4 (CTLA4) that is a co-stimulatory molecule for inhibition of T-cell activation and of Smad7 that is a regulatory factor of TGF-beta intracellular signaling. For 47 Japanese patients with PPP who had tonsillectomy, the skin lesion was improved in 87% of PPP patient at 12 months after tonsillectomy. In quantitative immunohistologic analysis, T-cell nodules on tonsillar tissues from PPP patients were more expanded than those from the patients with obstructive sleep apnea syndrome (OSAS) (P = 0.015), and there was a positive correlation between the enlargement and clinical improvement (r = 0.422, P = 0.021). Flow cytometric analysis showed that the numbers of CD4+CD25+ and CD4+CD29+ cells in tonsils from PPP patients increased significantly compared to those from OSAS patients (P = 0.017, P = 0.016, respectively). Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analyses with CD3+ tonsillar lymphocytes, we found that both expressions of Smad7 mRNA and protein were enhanced in PPP patients compared with OSAS patients (P = 0.03, P = 0.02, respectively), but expression of TGF-beta mRNA was not different between 2 groups. Although mRNA expression of CTLA4 was reduced in PPP patients compared with OSAS patients (P = 0.04), the CTLA4 surface protein expression was not different between 2 groups. These data suggest that helper T-cells are frequently activated in tonsils from PPP patients, and this activation may be related to unresponsiveness of TGF-beta1 by overexpression of Smad7. Such hyper-activation of T-cell may increase the risk of elicitation of self-reactive T-cell, being associated with pathogenesis of PPP.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation; B-Lymphocytes; CTLA-4 Antigen; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Japan; Male; Middle Aged; Palatine Tonsil; Psoriasis; RNA, Messenger; Smad7 Protein; T-Lymphocytes; Tonsillectomy; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Psoriasis is a disease characterized by an abnormal pattern of keratinocyte growth and differentiation. Malassezia furfur forms part of the normal human skin flora. It may also be involved in the pathogenesis of psoriasis. To define the role of M. furfur in the pathogenesis of psoriasis, we investigated how M. furfur regulates molecules involved in cell migration and proliferation. The experiments were performed using human keratinocytes and skin biopsies from M. furfur-positive and -negative psoriasis-affected patients. In addition, we examined the signal transduction mechanisms involved.. Western blot analysis was performed on human keratinocytes lysates treated or untreated with M. furfur and on biopsies from healthy and psoriasis patients. Signal transduction mechanisms involved were evaluated by electrophoretic mobility shift assay using the AP-1 inhibitor curcumin.. We found that M. furfur up-regulates transforming growth factor-beta1 (TGF-beta1), integrin chain, and HSP70 expression in human keratinocytes via AP-1-dependent mechanism. In the biopsies of M. furfur-positive psoriasis-affected patients, an increase in TGF-beta1, integrin chains, and HSP70 expression was found.. Our data suggest that M. furfur can induce the overproduction of molecules involved in cell migration and hyperproliferation, thereby favoring the exacerbation of psoriasis.

Topics: Blotting, Western; Cell Division; Cell Movement; Cells, Cultured; HSP70 Heat-Shock Proteins; Humans; Integrins; Keratinocytes; Malassezia; Psoriasis; Signal Transduction; Skin; Transcription Factor AP-1; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor beta1 (TGFbeta1), a potent keratinocyte growth inhibitor, has been shown to be overexpressed in keratinocytes in certain inflammatory skin diseases and has been thought to counteract the effects of other growth factors at the site of inflammation. Surprisingly, our transgenic mice expressing wild-type TGFbeta1 in the epidermis using a keratin 5 promoter (K5.TGFbeta1(wt)) developed inflammatory skin lesions, with gross appearance of psoriasis-like plaques, generalized scaly erythema, and Koebner's phenomenon. These lesions were characterized by epidermal hyperproliferation, massive infiltration of neutrophils, T lymphocytes, and macrophages to the epidermis and superficial dermis, subcorneal microabscesses, basement membrane degradation, and angiogenesis. K5.TGFbeta1(wt) skin exhibited multiple molecular changes that typically occur in human Th1 inflammatory skin disorders, such as psoriasis. Further analyses revealed enhanced Smad signaling in transgenic epidermis and dermis. Our study suggests that certain pathological condition-induced TGFbeta1 overexpression in the skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders.

Topics: Animals; Basement Membrane; Cell Proliferation; Cytokines; Female; Gene Expression; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Transgenic; Phenotype; Psoriasis; Signal Transduction; Skin; Transforming Growth Factor beta; Transforming Growth Factor beta1

Psoriasis is a common chronic cutaneous disease affecting 1-3% of general population. Its pathogenesis is not fully understood, but the involvement of several cytokines has clearly been established. The aim of the present study was to evaluate serum concentrations of transforming growth factor (TGF)-beta 1 in patients with psoriasis vulgaris and to correlate these concentrations with severity of psoriasis and several other clinical parameters. Sixty patients with psoriasis and 38 healthy persons (control group) were included into the study. TGF-beta 1 was measured by enzyme-linked immunosorbent assay (ELISA) using commercially available kits. Serum concentrations of TGF-beta 1 in patients with psoriasis were significantly increased compared with the controls (42.9+/-9.9 vs. 37.7+/-6.0 ng/mL, respectively, p=0.004). Patients with more severe disease (PASI <24 points) had significantly higher serum concentration of TGF-beta 1 than those with mild psoriasis (PASI<24 points; p<0.001). Moreover, serum TGF-beta 1 concentration significantly correlated with disease severity (p=0.001). In patients with pre-existing infections of the respiratory tract, the concentrations of serum TGF-beta 1 were significantly decreased (p=0.03). Since serum concentrations of TGF-beta 1 are increased in patients with psoriasis, TGF-beta 1 might be used as a marker of psoriasis activity.

Topics: Adolescent; Adult; Case-Control Studies; Female; Humans; Male; Middle Aged; Psoriasis; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1

Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony-stimulating factor (G-CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine-induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient who developed G-CSF-induced psoriasiform dermatitis by using quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8(+) T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on adjacent keratinocytes. As compared to normal skin (n = 7), there was an increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased expression of TGF-beta1, and a lack of IL-10, similar to the findings in active psoriasis (n = 8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non-professional immune functions.

Topics: Cytokines; Drug Eruptions; Epidermis; Gene Expression; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-10; Interleukin-12; Interleukin-12 Subunit p35; Interleukin-12 Subunit p40; Interleukin-8; Keratinocytes; Male; Middle Aged; Protein Subunits; Psoriasis; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Topics: Animals; Arthritis, Psoriatic; Humans; Immunosuppressive Agents; Immunotherapy; Psoriasis; Streptococcal Infections; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Psoriasis vulgaris is a chronic inflammatory disorder characterized by epidermal hyperproliferation. Transforming growth factor beta (TGFbetas) have a major antiproliferative action in epidermis.. We evaluated the distribution and levels of expression of TGFbeta isoforms and their receptors in psoriatic versus normal skin with the goal of discovering potential alterations in TGFbeta signal transduction associated with psoriasis.. Expression of TGFbeta isoforms and their receptors was analyzed in normal and psoriatic skin using immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. Furthermore, DNA synthesis was measured in normal keratinocytes transfected with a dominant-negative TGFbeta receptor II (TbetaRII) vector that eliminated most of the cytoplasmic TbetaRII domain.. Marked elevations in DNA synthesis, as assessed by BrdU incorporation and proliferating cell nuclear antigen (PCNA) immunoreactivity, were confirmed in psoriatic epithelial cells. Using immunohistochemistry and RT-PCR analysis, expression of TGFbeta2 and 3 was diminished in the psoriatic epidermis as compared with those observed in normal skin. With respect to TGFbeta receptors, expression of TbetaRI and II was markedly decreased in the psoriatic epidermis. In addition, levels of Smad2 mRNA were also decreased in psoriatic skin. Transfection of normal keratinocytes with the dominant-negative TbetaRII vector significantly elevated DNA synthesis as compared with keratincoytes transfected with control vector (under condition of TGFbeta addition), suggesting that the dominant-negative TbetaRII mutant inhibits the antiproliferative effects of TGFbeta.. The present investigation strongly suggest that the TGFbeta signaling pathway is downregulated in psoriatic skin and this situation leads to abnormal cell proliferation due to a functional decrease in growth regulation.

Topics: Adult; Aged; Case-Control Studies; Cell Division; Down-Regulation; Genes, Dominant; Humans; Immunohistochemistry; Keratinocytes; Middle Aged; Protein Isoforms; Protein Serine-Threonine Kinases; Psoriasis; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; Skin; Transfection; Transforming Growth Factor beta

Psoriasis is an inflammatory skin disorder with hyperproliferation of keratinocytes, that can be the result of insufficient inhibitory effect of transforming growth factors-beta (TGF-beta). The aim of this study was to evaluate an association between TGF-beta(1) and -beta(2) in plasma or scales from psoriatic lesions and the severity of the disease. TGF-beta concentrations were measured with an enzyme immunoassay in 41 patients with psoriasis. The mean plasma concentrations of TGF-beta(1) and TGF-beta(2) in patients were: 15.7 +/- 1.4 and 0.15 +/- 0.02 ng/ml respectively. It was also detectable in scales and varied from 24 to 1159 and from 0 to 2.95 pg/mg protein respectively. Plasma TGF-beta(1) correlated significantly with psoriasis area and severity index (PASI). Significant correlation was also demonstrated between TGF-beta(1) concentration in scales and sedimentation rate or the disease duration. There were no correlation between PASI and plasma TGF-beta(2), scales TGF-beta(1) and TGF-beta(2). The highest mean concentration of TGF-beta(1) in scales of patients with mild form of the disease (203 +/- 65 pg/mg protein) and the lowest in severe form (147 +/- 54 pg/mg protein) have been shown. These findings demonstrated association between PASI and plasma levels of TGF-beta(1), that should be considered as a possible indicator of psoriasis activity.

Topics: Adolescent; Adult; Aged; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Psoriasis; Skin; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2

Intraepidermal T lymphocytes are a critical element for sustaining the lesional pathology of psoriasis. Integrin alphaEbeta7 (CD103), a ligand for E-cadherin, may play a role in the localization of pathogenic T cells within the epidermis of psoriatic lesions. However, little information is available regarding alphaEbeta7 expression on intraepidermal T cells in psoriasis.. To examine alphaEbeta7 expression on intraepidermal T cells in psoriatic lesions and the regulation of alphaEbeta7 expression on T cells in response to cytokines.. T-cell expression of alphaEbeta7 was examined by immunohistochemistry and flow cytometry. In vitro regulation of alphaEbeta7 expression on CD4+ or CD8+ T cells purified from peripheral blood of healthy donors was also examined.. Immunohistochemical staining revealed expression of alphaEbeta7 on a greater proportion of epidermal T cells than dermal T cells. Nearly 30% of intraepidermal CD4+ T cells were found to express alphaEbeta7 on flow cytometry, whereas more than 80% of intraepidermal CD8+ T cells expressed this integrin. In contrast, few T cells expressed alphaEbeta7 in the peripheral blood of psoriatic patients. The in vitro culture experiment confirmed that alphaEbeta7 was preferentially expressed on CD8+ T cells after stimulation with anti-CD3 monoclonal antibodies. Addition of transforming growth factor-beta and interleukin-4 upregulated alphaEbeta7 expression on T cells, whereas interleukin 12 downregulated this. Furthermore, alphaEbeta7 expression on established memory CD8+ T cells was not so reversible as that on CD4+ T cells.. Preferential and stable expression of alphaEbeta7 on CD8+ T cells may be involved in the lesional pathology of psoriasis.

Topics: Adult; Aged; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Chronic Disease; Epidermis; Female; Flow Cytometry; Humans; Integrins; Interleukin-12; Interleukin-4; Male; Middle Aged; Psoriasis; Transforming Growth Factor beta

Activin A, a member of the transforming growth factor beta (TGF-beta) superfamily, affects keratinocyte proliferation and differentiation in vitro and in vivo. However, little is known about the mechanisms of activin action in keratinocytes, and its target genes have not been identified. In this study, we demonstrate that activin A and TGF-beta1 directly induce the expression and activity of Mad1, an antagonist of the c-Myc transcription factor, in the human HaCaT keratinocyte cell line. Expression and activity of Mad1 was strongly induced by both factors in keratinocytes, although the intensity of induction was different for activin A and TGF-beta1. To determine a possible role of activin and TGF-beta in the regulation of mad1 expression in vivo, we analysed its expression during cutaneous wound repair when high levels of these factors are present. Expression of mad1 mRNA and protein, but not of other mad genes, increased significantly after skin injury, particularly in polymorphonuclear leukocytes and in suprabasal keratinocytes of the hyperproliferative epithelium. Elevated levels of mad1 mRNA were also detected in the hyperthickened epidermis of psoriatic patients. Since Mad1 regulates proliferation and/or differentiation of various cell types, our results suggest that this transcription factor mediates at least in the part the anti-mitotic and/or differentiation-inducing activities of TGF-beta and activin in keratinocytes.

Topics: Activins; Adult; Aged; Animals; Blotting, Western; Cell Cycle Proteins; Cell Differentiation; Cell Division; Cell Line; Cell Nucleus; COS Cells; DNA; DNA, Complementary; Epidermal Cells; Epidermis; Humans; In Situ Hybridization; Keratinocytes; Mice; Mice, Inbred BALB C; Middle Aged; Neutrophils; Nuclear Proteins; Phosphoproteins; Psoriasis; Repressor Proteins; RNA, Messenger; Skin; Time Factors; Transcription Factors; Transfection; Transforming Growth Factor beta; Tumor Cells, Cultured; Wound Healing

Transforming growth factor (TGF) -beta has been suggested to be an effective inhibitor for abnormal keratinocyte growth in psoriasis. As a majority of the secreted TGF-beta are biologically latent complexes, activation is essential for TGF-beta-mediated cellular responses in vitro and in vivo. Objectives Here we report the response of the TGF-beta regulation system to 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], an active vitamin D3 analogue Patients/methods We studied two types of fibroblasts derived from normal and psoriatic lesional skin, using an enzyme-linked immunosorbent assay and Northern blotting techniques.. 1,25(OH)2D3 caused a dose-dependent induction of latent and active TGF-beta1 proteins in both cell cultures. The increases were significant over 72 h, but not within 48 h after stimulation. The time course of TGF-beta1 mRNA expression showed a biphasic response consisting of early ( approximately 1 h) and late phases ( approximately 96 h) of induction. Concomitant increases of TGF-beta2 and -beta3, other mammalian isoforms, were observed in the 1,25(OH)2D3-treated cells, but the kinetics were all different. Co-incubation with metabolic inhibitors, actinomycin D and cycloheximide, revealed that the early induction of TGF-beta1 mRNA by 1,25(OH)2D3 is dependent on de novo RNA synthesis, but not on RNA stabilization or protein synthesis. It seems likely to be a transient and negligible response given the absence of TGF-beta1 protein production. The late induction of TGF-beta1 mRNA was partially blocked by adding isoform-specific antibodies to TGF-beta1, -beta2 and -beta3, indicating TGF-beta autoregulation. Despite these marked responses, there were no significant differences in the TGF-beta expression between normal and psoriatic fibroblasts.. These results suggest that antiproliferative and anti-inflammatory effects of 1,25(OH)2D3 on psoriatic lesional skin may be mediated, at least in part, by a complex TGF-beta regulation in local dermal fibroblasts.

Topics: Administration, Topical; Adult; Blotting, Northern; Calcitriol; Cells, Cultured; Fibroblasts; Humans; Psoriasis; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

Endoglin is a glycoprotein which is predominantly expressed on endothelial cells. It is upregulated under inflammatory conditions as well as in skin lesions where endothelial cell proliferation occurs. Endoglin has the capacity to bind transforming growth factor beta (TGF-beta) and can reduce the bioavailability of TGF-beta. TGF-beta has a growth-inhibiting effect on keratinocytes and a restraining influence on the extravasation of peripheral white blood cells. In order to find out how endoglin is expressed in the margin zone of psoriatic plaques and how it correlates with the appearance of an inflammatory infiltrate, punch biopsies were taken from the margin zone of actively spreading psoriatic plaques in 8 patients. Indirect immunoperoxidase staining was performed using PAL-E (vascular endothelium), PN-E2 (anti-endoglin) and T11 (T-lymphocytes). In all patients it was found that the appearance of parakeratosis correlated with a clear increase of PN-E2 expression. PAL-E and PN-E2 expression was assessed, using a 5-point scale. Thus a tendency to decreased PN-E2 expression in uninvolved skin compared to PAL-E expression was found within the margin zone (1.6 +/- 0.4 and 2.2 +/- 0.4, respectively), whereas in involved skin PN-E2 expression and PAL-E expression were in agreement (2.6 +/- 0.5 and 2.6 +/- 0.5 respectively), suggesting that in the overt plaque all endothelium is in a so-called activated state. Also correlating with PN-E2 expression was the appearance of a huge dermal lymphocytic infiltrate and epidermal T-lymphocytic expression. The present study lends further support for a permissive role of endoglin expression in the development of the psoriatic lesion.

Topics: Adult; Antibodies, Monoclonal; Antigens, CD; Endoglin; Female; Humans; Immunoenzyme Techniques; Inflammation; Male; Middle Aged; Psoriasis; Receptors, Cell Surface; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Corneometry has been considered useful both to evaluate disease severity and to monitor psoriatic patients during treatment. However, a limitation of this technique is that the patient's age influences the corneometric determinations, thus reducing their clinical usefulness. The aim of this study was, therefore, to establish whether age normalization of the corneometric results may provide more reliable data for clinical use. Corneometric levels were determined in 10 plaque-type psoriatic patients, under standard conditions. Eight serum variables, including transforming growth factor-beta 1 and seven soluble membrane molecules, were assayed with commercially available immune-enzyme methods in the same patients, whose age and PASI scores were also recorded. The age normalization procedure improved all the correlation coefficients calculated on the lesional or non-lesional corneometric values versus the PASI scores as well as versus the other serum variables. This approach may render corneometric determinations more useful to evaluate disease status or treatment effect in patient groups with plaque-type psoriasis.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Cell Adhesion Molecules; Female; Humans; Immunoenzyme Techniques; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Psoriasis; Receptors, Interleukin-1; Severity of Illness Index; Sialoglycoproteins; Skin; Skin Tests; Transforming Growth Factor beta

T lymphocyte adhere to dermal microvascular endothelial cells (DMEC.) as the first step in their emigration from the blood vasculature into diseased skin. Earlier studies have shown that the adhesiveness of cultured DMEC. from normal skin for lymphocytes can be blocked by transforming growth factor-beta1 (TGF-beta1). In contrast, TGF-beta1 has no effect on the adhesive properties of DMEC from psoriatic plaques, and this response is attenuated by the addition of interleukin-4 (IL-4). In the present study, we show that both TGF-beta1 and TGF-beta2, and to a lesser extent TGF-beta3 isoforms block the ability of normal but not psoriatic DMEC to bind lymphocytes. Pretreatment with TGF-beta1 selectively inhibited the tumor necrosis factor-alpha(TNF-alpha)-stimulated expression of E-selecting on normal DMEC but had no psoriatic DMEC. Scatchard analysis revealed both low- and high-affinity receptors on normal DMEC. The baseline number of high-affinity TGF-beta receptors was significantly reduced on psoriatic DMEC, whereas IL-4 treatment of DMEC altered the binding affinity but not the number of receptors. The protein and mRNA transcripts of type I and type II TGF-beta receptor genes were detectable in psoriatic DMEC. A reduction in the autophosphorylation the TGF-beta type II receptor protein, a constitutively active serine/threonine kinase, however, was detected in psoriatic DMEC. These in vitro finding suggest that reduction of TGF-beta receptor expression and function may contribute to lymphocyte infiltration into psoriatic plaques in vivo by allowing dermal microvascular endothelium to escape form the negative regulation by TGF-beta.

Topics: Blotting, Northern; Cell Adhesion; Cross-Linking Reagents; E-Selectin; Endothelium, Vascular; Humans; Leukocytes, Mononuclear; Microcirculation; Phosphorylation; Psoriasis; Receptors, Transforming Growth Factor beta; Skin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Transforming growth factor-beta (TGF-beta) can act as a multi-functional regulator of both cell growth and differentiation. Three isoforms of TGF-betas, namely TGF-beta 1 TGF-beta 2 and TGF-beta 3, have been identified in human tissues. Previously we reported the expression of TGF-beta isoforms in normal human skin. However little is known about the role of TGF-beta isoforms in the pathogenesis of psoriasis. Using the TGF-beta precursor-specific antibodies to strengthen the specificity, we studied the immunohistochemical distribution of TGF-betas 1-3 in psoriatic skin. TGF-beta 2, which was found in the intercellular space of all the layers of the epidermis in normal human skin, was decreased in the psoriatic epidermis. The intensity of immunoreactivity has the tendency to decrease in the lower epidermis rather than in the upper epidermis of the transitional lesion. In contrast, TGF-beta 3 was present in the subepidermal area of the psoriatic skin as in the normal human skin. TGF-beta 1 was observed in neither epidermis nor dermis in both normal and psoriatic skin. Since TGF-beta is a potent growth inhibitor for human keratinocytes, the decrease of TGF-beta 2 in the epidermis of psoriatic skin may contribute to epidermal hyperplasia, a hallmark of psoriasis.

Topics: Humans; Immunohistochemistry; Protein Precursors; Psoriasis; Skin; Transforming Growth Factor beta

Psoriasis is a chronic skin disease characterized by epidermal hyperproliferation, disturbed differentiation, and inflammation. It is still a matter of debate whether the pathogenesis of psoriasis is based on immunological mechanisms, on defective growth control mechanisms, or possibly on a combination of both. Several in vivo cell biological differences between psoriatic lesional epidermis and normal epidermis have been reported. However, it is not clear whether these changes are causal or consequential. In case that keratinocytes from psoriatic patients have genetically determined deficiencies or polymorphisms with respect to autocrine growth regulation and the response to inflammatory cytokines, we hypothesize that these differences should be maintained in culture. Here we have started a systematic comparison of first passage keratinocytes cultured from normal skin and uninvolved psoriatic skin to address the question whether there are intrinsic differences in basic cell cycle parameters. In an established, defined culture system using keratinocyte growth medium (KGM) we have determined: (i) cell cycle parameters of exponentially growing keratinocytes, (ii) induction of quiescence by transforming growth factor beta 1 (TGF-beta 1) and (iii) restimulation from the G0-phase of the cell cycle. Bivariate analysis of lodo-deoxyuridine incorporation and relative DNA content was performed by flow cytometry. Within the limitations of this model no gross differences were found between normal and psoriatic keratinocytes with respect to S-phase duration (Ts), total cell cycle duration (Tc), responsiveness to TGF-beta 1 and the kinetics for recruitment from G0. In psoriatic keratinocytes we found a lower amount of cell in S-phase and a shorter duration of G1, compared to normal keratinocytes. The methodology developed here provides us with a model for further studies on differences between normal and psoriatic keratinocytes in their response to immunological and inflammatory mediators.

Topics: Cell Cycle; Cells, Cultured; Culture Media; Epidermal Cells; Humans; Keratinocytes; Psoriasis; Transforming Growth Factor beta

We studied the expression of the type II transforming growth factor-beta receptor mRNA in normal and psoriatic human skin in vivo. In situ hybridization analysis showed that its signals were expressed in the epidermal keratinocytes of the basal, the spinous and the granular layer, although no significant signals were observed in the fibroblasts or endothelial cells of the dermis. The follicular epithelium also expressed the type II transforming growth factor-beta receptor mRNA. There was no difference in the pattern of DNA expression between normal and psoriatic skin. These results suggest that the mRNA of the type II transforming growth factor-beta receptor is mainly expressed in the epithelial components of skin and controls the proliferation of the epidermis.

Topics: Endothelium; Epidermis; Fibroblasts; Gene Expression; Humans; In Situ Hybridization; Keratinocytes; Protein Serine-Threonine Kinases; Psoriasis; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Reference Values; RNA, Messenger; Skin; Transforming Growth Factor beta

Normal and chronic plaque psoriatic keratinocyte cultures were tested for their in vitro response to 2-200 ng/ml TNF-alpha and 0.1-10 ng/ml TGF-beta in a serum-free culture system. All normal and lesional psoriatic epidermal cell cultures showed a dose- and time-dependent inhibition of growth in response to TNF-alpha and TGF-beta. Inhibition in individual cultures was first seen at a concentration of 2 ng/ml for TNF-alpha and 0.1 ng/ml for TGF-beta at day 2, but became significant at 20 ng/ml and 1 ng/ml for TNF-alpha and TGF-beta respectively at days 2-6. This effect was statistically significant at days 3-4 for the group of normal (TNF-alpha and TGF-beta, n = 10, p < 0.01) and psoriatic cultures (TNF-alpha, n = 9, p < 0.01; TGF-beta, n = 7, p < 0.05). Epidermal cells from normal and psoriatic skin were inhibited to the same extent at the same optimal concentrations by each cytokine. Inhibition was abolished by the addition of specific antibody to each cytokine, whilst antibody to a different cytokine had no effect. Nuclear and/or nuclear membrane staining was observed with antibody to the p55 TNF receptor both in cultured keratinocytes and in the upper epidermal layers of both normal and psoriatic skin. In contrast, plasma membrane and cytoplasmic expression of the p55 TNF receptor was observed on macrophages and lymphocytes infiltrating psoriatic dermis. This study has shown that the growth of normal and psoriatic keratinocytes was equally inhibited by TNF-alpha and TGF-beta in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cell Division; Cell Nucleus; Humans; Keratinocytes; Lymphocytes; Macrophages; Nuclear Proteins; Psoriasis; Receptors, Tumor Necrosis Factor; Skin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The purpose of this study was to investigate and to compare, by in situ hybridization, gene expression of IL-1 beta, IL-8, TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-alpha, p53 and c-myc in lesions and in non-involved skin of patients with psoriasis. All lesional skin biopsies showed overexpression of IL-1 beta, IL-8 TGF-alpha mRNAs. IL-1 beta hybridization signals were strong in a small number of cells localized predominantly in the dermal papillae and in the suprapapillary epidermis. Overexpression of TGF-alpha was observed in all suprabasal keratinocytes, whereas strongly elevated IL-8 mRNA expression was found to be restricted to clusters of suprabasal keratinocytes. TGF-beta 3, p53 and c-myc transcripts were clearly detected in the epidermis of all biopsies, although expression levels were comparable in lesional and non-lesional skin.

Topics: Cytokines; Gene Expression; Genes, myc; Genes, p53; Genes, Tumor Suppressor; Humans; In Situ Hybridization; Interleukin-1; Interleukin-8; Proto-Oncogene Mas; Proto-Oncogenes; Psoriasis; Transforming Growth Factor alpha; Transforming Growth Factor beta

Normal skin and uninvolved and involved psoriatic skin specimens were maintained in vitro in organ culture. The 3-4 mm punch-biopsied skin specimens were put freely into the culture medium with or without fetal calf serum, under an atmosphere of 95% O2 plus 5% CO2, and rotated at 60 rpm at 37 degrees C. In the serum-free culture medium (vitamin A-free) granular layers appeared in the involved psoriatic epidermis in culture. Addition of TGF-alpha caused normal skin and uninvolved and involved psoriatic skin specimens to become acanthotic and to degenerate easily almost to the full thickness of the epidermal layer in proportion to increasing concentrations of TGF-alpha as well as with the duration of the culture, but without disappearance of their granular layers. TGF-beta caused the normal skin and uninvolved psoriatic skin specimens to become thinned without disappearance of granular layers, but caused the involved psoriatic skin specimens to be thinned without appearance of granular layers in serum-containing medium or with their disappearance in the serum-free medium. TGF-beta also antagonized the acanthotic and degenerative effect of TGF-alpha. The results suggest that TGF-alpha and TGF-beta may partially be related to the induction of psoriatic epidermal lesions.

Topics: Humans; Organ Culture Techniques; Psoriasis; Skin; Transforming Growth Factor alpha; Transforming Growth Factor beta

Production of inhibitor(s) of IL-1 activity can be induced in keratinocytes by exposure to UVB. We describe in this study the characterization of an endogenous constitutively expressed IL-1 inhibitor which is present in extracts of human psoriatic epidermal keratome biopsies. Size-fractionated extracts of normal human epidermis did not reveal IL-1 inhibitory factor(s) activity in normal epidermis. Psoriatic epidermal extracts, however, contained virtually no IL-1 bioactivity and inhibited the activity of recombinant human IL-1 beta. This IL-1 inhibitor has a molecular weight of approximately 30 kDa and a pI of 5.3, as revealed by fast protein liquid chromatography size fractionation and chromatofocusing of psoriatic epidermal extracts. IL-1 inhibitory activity was not blocked by neutralizing anti-TGF beta monoclonal antibody. It did not have any inhibitory effect upon normal cellular proliferation but could block the IL-1 induction of IL-2 production by LBRM.33 cells as late as 4 h after exposure of LBRM.33 cells to IL-1. Thus, in vivo human psoriatic epidermis expresses an IL-1 inhibitor that specifically inhibits IL-1 activity but which appears distinct from previously described UV-induced epidermal IL-1 inhibitory activity or TGF beta.

Topics: Biopsy; Cell Division; Chromatography, Liquid; Cytosol; Humans; Interleukin-1; Interleukin-2; Keratinocytes; Psoriasis; Thymus Gland; Tissue Extracts; Transforming Growth Factor beta

Fresh and cultured human Langerhans cells display disparate functional programs, based on their capacities to activate autologous and allogeneic T cells, and with respect to their susceptibility to inhibition by transforming growth factor-beta (TGF beta). We have compared the functional properties of epidermal antigen-presenting cells (APC) procured from uninvolved and involved skin of patients with psoriasis with fresh and cultured normal epidermal cells. Freshly obtained psoriatic epidermal APC resembled cultured normal epidermal cells in their superior capacity to activate syngeneic and allogeneic T cells; fresh normal epidermal cells failed to activate syngeneic T cells, and induced only modest proliferation among allogeneic T cells. The modest T-cell--activating properties of fresh, normal epidermal cells were not suppressed by TGF beta, whereas the T-cell--activating potential of psoriatic epidermal cells, cultured normal epidermal cells, and blood APC was inhibited approximately 50% by TGF beta. Thus, fresh psoriatic epidermal APC resemble cultured normal epidermal cells functionally. Because these properties are already evident in cells obtained from uninvolved psoriatic skin, the "cultured" functional phenotype of epidermal APC in this disease may precede the appearance of active psoriatic skin lesions. Surface marker analysis of normal and psoriatic epidermal cell suspensions revealed that virtually all of the bone marrow--derived cells in normal epidermal cell suspensions were conventional (CD1+) Langerhans cells, whereas CD1+ cells comprised only a minority of bone marrow--derived (CD45+) cells in psoriatic epidermis. It is speculated that some of the CD1-, CD45+ cells in psoriatic epidermis may be Langerhans cells that have lost their "fresh" phenotype. These data indicate that an abnormality in epidermal APC function exists in psoriatic skin--even before clinical lesions develop, and we speculate that the abnormal capacity of psoriatic epidermal APC to activate syngeneic T cells may be important in the expression of keratinocyte pathology. Because psoriatic epidermal APC functions were profoundly inhibited in vitro by treatment with cyclosporin A, the effectiveness of this drug in psoriasis may be due in part to its ability to inhibit epidermal antigen-presenting cell function in vivo.

Topics: Aged; Antigen-Presenting Cells; Cells, Cultured; Cyclosporins; Epidermal Cells; Humans; Langerhans Cells; Lymphocyte Activation; Middle Aged; Phenotype; Psoriasis; Skin; T-Lymphocytes; Transforming Growth Factor beta