Lnc-ITSN1-2 promotes rheumatoid arthritis fibroblast-like synoviocytesproliferation and inflammation while represses apoptosis via positive regulation of IL-23R/JAK/STAT pathway, and correlates with increased disease risk and activity
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ORGANISM(S): Homo sapiens
PROVIDER: GSE129934 | GEO | 2019/04/18
REPOSITORIES: GEO
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Project description:Rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)‐6 signaling and Janus kinase (JAK)–signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint‐specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL‐6.Hip or knee RA FLS were obtained after arthroplasty. Previously published datasets on epigenetic landscape of FLS were mined to identify joint‐specific IL‐6–related epigenomic differences. RNA sequencing was performed on five RA hip and five knee FLS treated with or without IL‐6. Differential gene expression was determined using edgeR software. STAT3 phosphorylation was measured using bead assays. Sensitivity to tofacitinib was evaluated by measuring CCL2 inhibition using quantitative polymerase chain reaction. Assay for Transposase‐Accessible Chromatin sequencing and histone chromatin immunoprecipitation sequencing datasets from RA FLS were analyzed to identify epigenomic differences between hip and knee. Differential chromatin accessibility was associated with IL‐6, IL‐6R, and JAK1 genes. H3K27ac was also differentially marked at other JAK‐STAT–related genes, including STAT3‐STAT5A region. Principal component analysis of RNA sequencing data confirmed segregation between RA hip and knee FLS under basal conditions, that persisted following IL‐6 treatment. STAT3 phosphorylation after IL‐6 was significantly higher in knee than hip FLS and was highly correlated with JAK1 protein levels. Knee FLS were less sensitive to the JAK inhibitor tofacitinib than hip FLS. RA hip and knee FLS have distinct transcriptomes, epigenetic marks, and STAT3 activation patterns in the IL‐6 pathway. These joint‐specific differences might contribute to a differential clinical response in individual joints to targeted therapies such as JAK inhibitors.
2020-01-11 | GSE143443 | GEO
Project description:Lnc-ITSN1-2 promotes rheumatoid arthritis fibroblast-like synoviocytesproliferation and inflammation while represses apoptosis via positive regulation of IL-23R/JAK/STAT pathway, and correlates with increased disease risk and activity
| PRJNA533228 | ENA
Project description:Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10?mg twice daily or placebo for 28?days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.NCT00976599.
| S-EPMC4431345 | biostudies-other
Project description:ObjectiveRheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)-6 signaling and Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint-specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL-6.MethodsHip or knee RA FLS were obtained after arthroplasty. Previously published datasets on epigenetic landscape of FLS were mined to identify joint-specific IL-6-related epigenomic differences. RNA sequencing was performed on five RA hip and five knee FLS treated with or without IL-6. Differential gene expression was determined using edgeR software. STAT3 phosphorylation was measured using bead assays. Sensitivity to tofacitinib was evaluated by measuring CCL2 inhibition using quantitative polymerase chain reaction.ResultsAssay for Transposase-Accessible Chromatin sequencing and histone chromatin immunoprecipitation sequencing datasets from RA FLS were analyzed to identify epigenomic differences between hip and knee. Differential chromatin accessibility was associated with IL-6,IL-6R, and JAK1 genes. H3K27ac was also differentially marked at other JAK-STAT-related genes, including STAT3-STAT5A region. Principal component analysis of RNA sequencing data confirmed segregation between RA hip and knee FLS under basal conditions, that persisted following IL-6 treatment. STAT3 phosphorylation after IL-6 was significantly higher in knee than hip FLS and was highly correlated with JAK1 protein levels. Knee FLS were less sensitive to the JAK inhibitor tofacitinib than hip FLS.ConclusionRA hip and knee FLS have distinct transcriptomes, epigenetic marks, and STAT3 activation patterns in the IL-6 pathway. These joint-specific differences might contribute to a differential clinical response in individual joints to targeted therapies such as JAK inhibitors.
| S-EPMC6917316 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced inter-patient heterogeneity. To characterize RA at the molecular level and to uncover key pathomechanisms, we performed whole-genome gene expression analyses. Synovial tissues from rheumatoid arthritis patients were compared to those from osteoarthritis patients and to normal donors. Keywords: disease state analysis
2004-11-04 | GSE1919 | GEO
Project description:Joint Location-Specific JAK-STAT Signaling in Rheumatoid Arthritis Fibroblast-like Synoviocytes
| PRJNA600510 | ENA
Project description:Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFN??p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFN??p-STAT5, IL-10?p-STAT1) or increased (e.g., IL-6?STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFN??p-STAT5 signaling and IL-10?p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.
| S-EPMC7808603 | biostudies-literature
Project description:BackgroundRheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown.MethodsThe DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5 mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot.ResultsShikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin+cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes.ConclusionShikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis.
| S-EPMC8487562 | biostudies-literature
Project description:Rheumatoid arthritis: aortic biopsies
| PRJNA432552 | ENA
Project description:Analysis of biopsies of the ascending aorta from coronary artery disease patients with and without rheumatoid arthritis
2018-03-19 | GSE110008 | GEO