transforming-growth-factor-beta and Arthritis--Psoriatic

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Topics: Arthritis, Psoriatic; Cytokines; Forkhead Transcription Factors; Humans; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factors

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

The development of novel treatment strategies of immune-mediated inflammatory arthritis (IMIA) is still a clinical unmet need. The mitogen-activated protein kinase (MAPK) pathway is activated by environmental stressors, growth factors and inflammatory cytokines. However, the inhibition of central MAPK proteins has so far had undesirable side effects. The MAPK-activated protein kinase 2 (MK2) is a downstream mediator in the MAPK signaling pathway.. The objective of this study was to explore the effects of a small molecule inhibiting MK2 on synovial fluid mononuclear cells from patients with IMIA.. Synovial fluid mononuclear cells (SFMCs) were obtained from a study population consisting of patients with active rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or psoriatic arthritis (PsA) with at least one swollen joint (for obtaining synovial fluid) (n = 11). SFMCs were cultured for 48 h with and without the MK2 inhibitor CC0786512 at 1000 nM, 333 nM and 111 nMand cell free supernatants were harvested and frozen before they were analyzed by the Olink proseek multiplex interferon panel.. In SFMCs cultured for 48 h, the MK2 inhibitor decreased the production of chemokine (C-X-C motif) ligand 9 (CXCL9) (P < 0.001), CXCL10 (P < 0.01), hepatocyte growth factor (HGF) (P < 0.01), CXCL11 (P < 0.01), tumor necrosisfactor-like weak inducer of apoptosis (TWEAK) (P < 0.05), and interleukin 12B (IL-12B) (P < 0.05) and increased the production of CXCL5 (P < 0.0001), CXCL1 (P < 0.0001), CXCL6 (P < 0.001), transforming growthfactoralpha (TGFα) (P = 0.01), monocyte-chemotactic protein 3 (MCP-3) (P < 0.01), latency-associated peptide (LAP) TGFβ (P < 0.05) dose-dependently.. This study reveals the downstream effects of MK2 inhibition on the secretory profile of SFMCs. Specifically, C-X-C motif chemokine receptors 3 (CXCR3) chemokines were decreased and CXCR2 chemokines were increased. This shift in the chemokine milieu may be one of the mechanisms behind the anti-inflammatory effects of MK2 inhibitors.

Topics: Anti-Inflammatory Agents; Arthritis, Psoriatic; Cells, Cultured; Chemokines; Hepatocyte Growth Factor; Humans; Interferons; Interleukin-12 Subunit p40; Ligands; Mitogen-Activated Protein Kinases; Receptors, Interleukin-8B; Synovial Fluid; Synovial Membrane; Transforming Growth Factor alpha; Transforming Growth Factor beta

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

CD248 is a transmembrane glycoprotein expressed on the surface of activated perivascular and fibroblast-like cells. This study was undertaken to explore the function of CD248 and its cytoplasmic domain in arthritis.. Synovial tissue biopsy samples from healthy controls, from patients with psoriatic arthritis (PsA), and from patients with rheumatoid arthritis (RA) were stained for CD248. Transgenic mice that were CD248-deficient (CD248-knockout [CD248(KO/KO) ]) or mice with CD248 lacking the cytoplasmic domain (CD248(CyD/CyD) ) were generated. Collagen antibody-induced arthritis (CAIA) was induced in these mice and in corresponding wild-type (WT) mice as controls. Clinical signs and histologic features of arthritis were evaluated. Cytokine levels were determined by enzyme-linked immunosorbent assay, and the number of infiltrating inflammatory cells was quantified by immunohistochemistry. In vitro studies were performed with fibroblasts from CD248-transgenic mouse embryos to explain the observed effects on inflammation.. Immunostaining of synovium from patients with PsA and patients with RA and that from mice after the induction of CAIA revealed strong CD248 expression in perivascular and fibroblast-like stromal cells. CD248(KO/KO) and CD248(CyD/CyD) mice had less severe arthritis, with lower plasma levels of proinflammatory cytokines, as compared with WT controls. Moreover, the joints of these mice had less synovial hyperplasia, reduced accumulation of inflammatory cells, and less articular cartilage and bone damage. Tumor necrosis factor α-induced monocyte adhesion to CD248(CyD/CyD) fibroblasts was impaired. CD248(CyD/CyD) fibroblasts exhibited reduced expression of hypoxia-inducible factor 1α, placental growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9 activity in response to transforming growth factor β.. CD248 contributes to synovial hyperplasia and leukocyte accumulation in inflammatory arthritis, the effects of which are mediated partly via its cytoplasmic domain. CD248 is therefore a potential new target in the treatment of arthritis.

Topics: Adult; Animals; Antigens, CD; Antigens, Neoplasm; Arthritis, Experimental; Arthritis, Psoriatic; Arthritis, Rheumatoid; Biopsy; Cell Adhesion; Cytokines; Cytoplasm; Disease Models, Animal; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Placenta Growth Factor; Pregnancy Proteins; Synovial Membrane; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To examine angiogenic growth factors in patients with early, untreated inflammatory arthritides and controls.. Synovial membrane (SM) infiltrate and Ang1, Ang2, and vascular endothelial growth factor (VEGF) mRNA and protein expression were examined using immunohistochemistry and in situ hybridization. Synovial fluid (SF) VEGF, transforming growth factor-beta (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) protein were measured by ELISA. Vascular morphology was assessed at arthroscopy.. Ang2 mRNA and protein expression was observed in early psoriatic arthritis (PsA) and rheumatoid arthritis (RA) SM. Expression of Ang2 and VEGF was significantly greater in early PsA SM and correlated strongly. SF VEGF and TGF-beta 1 concentrations were also significantly higher in early PsA compared to RA. Distinct vascular morphology, with tortuous vessels in PsA, correlated with microscopic vascular scores (r = 0.54, p = 0.005) and VEGF levels (r = 0.51, p = 0.01). Ang1 mRNA and protein expression was observed, but concentrations were markedly lower than for Ang2 and VEGF. Clinical disease activity, SM infiltration, and SF TNF-alpha concentrations were similar in both groups.. This is the first report of angiopoietin expression in early inflammatory arthritis. There is a close relationship between angiopoietins, VEGF, TGF-beta, and vascular morphology. There is differential angiogenesis at an early stage of inflammation, with major pathogenic and therapeutic implications.

Topics: Adult; Aged; Angiogenesis Inducing Agents; Angiopoietin-1; Angiopoietin-2; Arthritis, Psoriatic; Arthritis, Rheumatoid; Arthroscopy; Endothelial Growth Factors; Humans; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Lymphokines; Membrane Glycoproteins; Middle Aged; RNA, Messenger; Synovial Membrane; Synovitis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Topics: Animals; Animals, Genetically Modified; Antigen Presentation; Arthritis, Psoriatic; Arthritis, Reactive; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Crohn Disease; Cystine; Dimerization; Fibrillins; Genetic Predisposition to Disease; Histocompatibility Antigens Class I; HLA-B27 Antigen; Humans; Lung; Lymphocyte Activation; Marfan Syndrome; Mice; Microfilament Proteins; Models, Immunological; Organ Specificity; Protein Conformation; Rats; Sacroiliac Joint; Spondylitis, Ankylosing; Stress, Mechanical; Transforming Growth Factor beta; Uveitis, Anterior

The main objective was to investigate the expression of platelet derived growth factor (PDGF) receptors, and production of growth factors and cytokines from psoriatic skin and synovium derived fibroblasts.. Fibroblast cultures were established from normal and psoriatic skin and synovium. Confluent cultures of fibroblasts were used for a receptor binding assay for PDGF, and then extracts were run on Western blot. The amount of immunoreactive A and B chain peptides present was determined with specific A or B chain antisera. Production of interleukin 1 beta and PDGF-beta was accomplished by neutralization with the use of commercially available antisera. A functional assay was used to measure transforming growth factor-beta (TGF-beta).. There was an increased expression of the beta PDGF receptor in the psoriatic fibroblasts. Interleukin 1 beta and PDGF-beta production by psoriatic fibroblasts was also increased. However, TGF-beta production was similar in normal and psoriatic fibroblasts.. Our data demonstrate an increased expression of beta PDGF receptor, and production of IL-1 beta and PDGF by psoriatic fibroblasts. The findings provide further support for an active role of this cell line in the pathogenesis of psoriasis and psoriatic arthritis.

Topics: Adult; Arthritis, Psoriatic; Blotting, Western; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Growth Substances; Humans; Male; Middle Aged; Receptors, Platelet-Derived Growth Factor; Transforming Growth Factor beta