transforming-growth-factor-beta and Dermatitis

Epidermal lipid synthesis and metabolism are regulated by nuclear hormone receptors (NHR) and in turn epidermal lipid metabolites can serve as ligands to NHR. NHR form a large superfamily of receptors modulating gene transcription through DNA binding. A subgroup of these receptors is ligand-activated and heterodimerizes with the retinoid X receptor including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR) and pregnane X receptor (PXR). Several isotypes of these receptors exist, all of which are expressed in skin. In keratinocytes, ligand activation of PPARs and LXRs stimulates differentiation, induces lipid accumulation, and accelerates epidermal barrier regeneration. In the cutaneous immune system, ligand activation of all three receptors, PPAR, LXR, and PXR, has inhibitory properties, partially mediated by downregulation of the NF-kappaB pathway. PXR also has antifibrotic effects in the skin correlating with TGF-beta inhibition. In summary, ligands of PPAR, LXR and PXR exert beneficial therapeutic effects in skin disease and represent promising targets for future therapeutic approaches in dermatology. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Topics: Animals; Dermatitis; Epidermis; Homeostasis; Humans; Lipid Metabolism; Liver X Receptors; Orphan Nuclear Receptors; Peroxisome Proliferator-Activated Receptors; Pregnane X Receptor; Receptors, Steroid; Transforming Growth Factor beta

The functions of transforming growth factor beta-1(TGFbeta1) are cell-context specific. We have found that TGFbeta1 expression in human skin squamous cell carcinoma (SCC) samples has two distinct distribution patterns: (1) either predominantly in suprabasal layers or (2) throughout tumor epithelia including basal proliferative cells. To understand whether the spatial TGFbeta1 expression patterns affect its functions, we have generated several keratinocyte-specific transgenic mouse models in which TGFbeta1 overexpression can be induced either predominantly in the suprabasal epidermis or in the basal layer of the epidermis and hair follicles. Suprabasal TGFbeta1 overexpression inhibits keratinocyte proliferation, suppresses skin carcinogenesis at early stages, but promotes tumor invasion at later stages. In contrast, TGFbeta1 overexpression in the basal layer of the epidermis and hair follicles causes a severe inflammatory skin disorder and epidermal hyperproliferation. Given the importance of inflammation in cancer development, our data suggest that TGFbeta1-induced skin inflammation may override its tumor suppressive effect at early stages during skin carcinogenesis. This hypothesis is further suggested by our recent study that Smad3 knockout mice are resistant to skin chemical carcinogenesis at least in part via abrogation of endogenous TGFbeta1-induced inflammation. This review intends to summarize current insights into the role of TGFbeta1 in skin inflammation and carcinogenesis.

Topics: Animals; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Dermatitis; Homeostasis; Humans; Mice; Mice, Transgenic; Skin Neoplasms; Transforming Growth Factor beta

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

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

Integrins avβ6 and avβ8 are expressed by keratinocytes and transactivate latent TGFβ. In a murine model, integrin mediated activation of TGFβ has been shown to be critical in maintaining skin homeostasis, specifically playing roles in epidermal retention of Langerhans cells and resident memory cells T cells (Trm).. We examine expression of Integrins β6 and β8 in human skin, inflammatory skin disease, benign nevi, and melanoma and hypothesize that integrin expression is dysregulated in disease.. Using immunohistochemistry, we stained tissue from normal human skin (n = 8), psoriasis (n = 6), atopic dermatitis (n = 6), lichen planus (n = 5), benign nevi (n = 24), and melanoma (n = 25) with anti-integrin β6 and anti-integrin β8 to survey expression pattern. We also performed a retrospective chart review in the melanoma cohort to examine if integrin β6 and β8 expression was associated with increased Breslow depth and worse prognostic staging.. Here, we show that human keratinocytes express integrins β6 and β8, similar to murine keratinocytes. We also found that inflammatory skin conditions have increased Integrin β6, but not Integrin β8 expression. Furthermore, we identified that melanomas have greatly increased expression of integrin β8 compared to nevi. Additionally, high expression of integrin β8 was correlated with greater Breslow depth at diagnosis and with worse prognostic staging.. These findings demonstrate that like murine keratinocytes, human keratinocytes express integrin β6 and β8 under steady state conditions. Moreover, altered integrin expression may participate in the development or maintenance of cutaneous inflammation as well as tumor immune evasion.

Topics: Animals; Dermatitis; Humans; Integrin beta Chains; Integrins; Melanoma; Melanoma, Cutaneous Malignant; Mice; Nevus; Retrospective Studies; Skin Neoplasms; Transforming Growth Factor beta

Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Cells, Cultured; Dermatitis; Dermis; Disease Models, Animal; Fibroblasts; Gene Expression; GTP-Binding Proteins; Humans; Interferon Type I; Interferon-gamma; Lupus Erythematosus, Cutaneous; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myxovirus Resistance Proteins; Poly I-C; Scleroderma, Systemic; Toll-Like Receptor 3; Transforming Growth Factor beta

Regulatory T cells (Tregs) are crucial for the induction and maintenance of self-tolerance and are present in peripheral tissues such as skin and gut under normal, noninflamed conditions. We report isolation and expansion of the Treg population resident in normal human skin. Cutaneous Tregs expressed high levels of CD25, L-selectin, GITR, FOXP3, and intracellular CTLA-4, low levels of CD69, and high levels of the skin-homing addressins CLA, CCR4, and CCR6. Skin Tregs suppressed the proliferation of CD25(lo) T cells from the same skin sample in response to CD3 and CD28 antibodies. Suppression was dependent on cell contact and not affected by neutralizing antibodies to interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Surprisingly, cutaneous Tregs proliferated in an antigen-independent manner when cultured in contact with dermal fibroblasts and IL-15, conditions similar to those found in chronically inflamed skin. We hypothesize that local proliferation of Tregs may occur within inflamed skin and could serve as a brake for cutaneous inflammation as well as a mechanism for the homeostatic proliferation of natural Tregs that has been observed within intact organisms.

Topics: Adenosine Deaminase; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Biomarkers; Blood; CD3 Complex; Cell Communication; Cell Division; Coculture Techniques; CTLA-4 Antigen; Dermatitis; Dipeptidyl Peptidase 4; Fibroblasts; Forkhead Transcription Factors; Glucocorticoid-Induced TNFR-Related Protein; Glycoproteins; Homeostasis; Humans; Immunophenotyping; Interleukin-10; Interleukin-15; Interleukin-2 Receptor alpha Subunit; L-Selectin; Lectins, C-Type; Membrane Glycoproteins; Models, Immunological; Receptors, CCR4; Receptors, CCR6; Receptors, Chemokine; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; Skin; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Our aim was to study the correlation between plasma transforming growth factor (TGF)-beta1 level and radiation-induced mucositis and dermatitis in nasopharyngeal carcinoma (NPC) patients.. Blood samples obtained from patients treated with concurrent chemo-radiotherapy (CCRT) were divided into two groups according to the pre-treatment plasma TGF-beta1 level (> or =7.5 ng/ml as group 1 and < 7.5 ng/ml as group 2). Enzyme-linked immunosorbent assay (ELISA) was used for the measurement of the TGF-beta1 level. Radiation toxicity was evaluated according to Radiation Treatment Oncology Group criteria. Data were analyzed by the generalized estimation equation method.. TGF-beta1 levels of group 1 patients were decreased significantly (P = 0.002) at the end of the treatment. The rate of decrease was 0.12 ng/ml per fraction (P = 0.02). The average TGF-beta1 level in patients who suffered acute radiation morbidity (grade > or =2) was significantly higher (P = 0.0057) than that of those who suffered less (grade < 2).. A lower pre-treatment plasma TGF-beta1 level and the grade of radiation toxicity both appeared to contribute to the elevated plasma TGF-beta1 after CCRT.

Topics: Antineoplastic Agents; Combined Modality Therapy; Dermatitis; Humans; Mouth Mucosa; Nasopharyngeal Neoplasms; Radiation Injuries; Radiotherapy; Stomatitis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta is responsible for triggering a cascade of events leading to fibrosis in scleroderma. The Smads are intracellular signal transducers recently shown to mediate fibroblast activation and other profibrotic responses elicited by transforming growth factor-betain vitro. To understand better the involvement of Smads in the pathogenesis of fibrosis, we examined Smad expression and activation in situ in a murine model of scleroderma. Bleomycin injections induced striking dermal infiltration with macrophages by 3 d, and progressive fibrosis by 2 wk. Infiltrating macrophages and resident fibroblasts expressed Smad3, the positive mediator for transforming growth factor-beta responses. Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3. Furthermore, phosphorylated Smad2/3 in fibroblasts was detected even after the resolution of inflammation. Expression of Smad7, the endogenous inhibitor of transforming growth factor-beta/Smad signaling, was strongly induced in dermal cells by transforming growth factor-beta, but not by bleomycin injections. Collectively, these results indicate that bleomycin-induced murine scleroderma is associated with rapid and sustained induction of transforming growth factor-beta/Smad signaling in resident dermal fibroblasts. Despite apparent activation of the intracellular transforming growth factor-beta signaling pathway in the lesional dermis, the expression of transforming growth factor-beta-inducible Smad7 was not upregulated. In light of the critical function of Smad7 as an endogenous inhibitor of Smad signaling that restricts the duration and magnitude of transforming growth factor-beta responses, and as a mediator of apoptosis, relative Smad7 deficiency observed in the present studies may account for sustained activation of transforming growth factor-beta/Smad signaling in lesional tissues. These findings raise the possibility that Smads plays an important part in the pathogenesis of fibrosis, and may therefore represent targets for selective anti-fibrotic interventions.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies; Bleomycin; Cells, Cultured; Dermatitis; Disease Models, Animal; DNA-Binding Proteins; Female; Fibroblasts; Mice; Mice, Inbred C3H; Phosphorylation; Scleroderma, Systemic; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad7 Protein; Trans-Activators; Transforming Growth Factor beta

Advances in the treatment of allergic disorders require elucidation of the autoregulatory immune systems induced in averting detrimental inflammatory responses against invading foreign Ags. We previously reported that excessive Ags intruding through the airway mucosa induce a subset of regulatory CD4+ T cells secreting TGF-beta in the regional mediastinal lymph nodes (MLNs), which inhibits Th2 cells and subsequent eosinophilic inflammation in the trachea. In the present experiments we examined whether and in what mechanisms TGF-beta-secreting CD4+ T cells in the MLNs regulate Th cell-mediated skin inflammation using a previously established murine model. Th1 or Th2 cells injected s.c. into ear lobes of naive mice induced swelling, whereas the concomitant local injection of MLN cells suppressed the inflammation. The suppressor activities of MLN cells were markedly neutralized by anti-TGF-beta mAb and were mimicked by rTGF-beta. The MLN cell- and rTGF-beta-induced inhibition was reversed by anti-IL-10 mAb significantly in Th1-induced inflammation and only partially in Th2-induced inflammation. rIL-10 reduced Th-induced ear swelling, although higher doses of rIL-10 were required in Th2-induced one. Thus, allergen-specific TGF-beta-producing CD4+ T cells induced in the respiratory tract controlled cutaneous inflammatory responses by Th1 or Th2 cells either directly by TGF-beta or indirectly through IL-10 induction. From a clinical standpoint, these observations might explain the mechanism of spontaneous regression in some patients with atopic dermatitis, which exhibits both Th1- and Th2-mediated skin inflammation in response to airborne protein Ags.

Topics: Animals; CD4-Positive T-Lymphocytes; Cells, Cultured; Dermatitis; Dermatitis, Atopic; Immune Tolerance; Interleukin-10; Lymph Nodes; Male; Mediastinum; Mice; Mice, Inbred BALB C; Ovalbumin; Th1 Cells; Th2 Cells; Trachea; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta) regulates cellular growth and differentiation and stimulates the synthesis and secretion of protein constituents of the extracellular matrix. Three isoforms of TGF-beta have been found in mammals. Although the biological activities of TGF-beta 1, TGF-beta 2, and TGF-beta 3 are similar at the level of cell culture, distinct in vivo functions for these molecules are emerging. To gain insight into the role of each isoform in wound repair, antibodies specific for each isoform of TGF-beta were used to examine excisional wound repair. Marked differences in the temporal and spatial relationships for immunoreactive TGF-beta 1, -beta 2, and -beta 3 were noted throughout the repair process. TGF-beta 2 and TGF-beta 3 were prevalent by 24 hours after excisional wounding, and strong immunoreactivity was observed in the migrating epidermis. Subtle changes in immunoreactivity occurred for TGF-beta 2 and TGF-beta 3 in cells of the epidermal appendages, mesenchymal derivatives, granulation tissue, and the underlying dermis throughout wound repair. In contrast, TGF-beta 1 was not associated with any undifferentiated cells and was not present in the dermis and most dermal structures in both nonwounded skin or wounds until day 5 after wounding, when re-epithelialization was complete. Following re-epithelialization, TGF-beta 2 and TGF-beta 3 were present in all four layers of stratum corneum of the differentiating epidermis. All three TGF-beta isoforms were present in mesenchymal cells and basal lamina, suggesting their role in the modulation of dermal-epidermal interaction during wound repair. Our observations support individual in vivo function for TGF-beta isoforms in cutaneous wound repair.

Topics: Animals; Basement Membrane; Dermatitis; Epithelium; Immunoenzyme Techniques; Skin; Swine; Transforming Growth Factor beta; Wound Healing