scholarly journals Heat shock of rabbit synovial fibroblasts increases expression of mRNAs for two metalloproteinases, collagenase and stromelysin.

1989 ◽  
Vol 108 (6) ◽  
pp. 2037-2043 ◽  
Author(s):  
B A Vance ◽  
C G Kowalski ◽  
C E Brinckerhoff
Keyword(s):  
Rheumatoid Arthritis ◽  
Heat Shock ◽  
Mrna Expression ◽  
Synovial Fibroblasts ◽  
Concomitant Treatment ◽  
Hsp 70 ◽  
Inflammatory Stress ◽  
Monolayer Cultures ◽  
All Trans Retinoic Acid ◽  
Lower Temperature

Two metalloproteinases, collagenase and stromelysin, are produced in large quantities by synovial fibroblasts in individuals with rheumatoid arthritis. These enzymes play a major role in the extensive destruction of connective tissue seen in this disease. In this study, we show that heat shock of monolayer cultures of rabbit synovial fibroblasts increases expression of mRNA for heat shock protein 70 (HSP-70), and for collagenase and stromelysin. We found that after heat shock for 1 h at 45 degrees C, the mRNA expression for HSP-70 peaks at 1 h and returns to control levels by 3 h. Collagenase and stromelysin mRNA expression is coordinate, reaching peak levels at 3 h and returning to control levels by 10 h. The increase in mRNA is paralleled by an increase in the corresponding protein in the culture medium. 3 h of heat shock at a lower temperature (42 degrees C) is also effective in inducing collagenase and stromelysin mRNAs. Concomitant treatment with phorbol myristate acetate (PMA; 10(-8) or 10(-9) M) and heat shock is not additive or synergistic. In addition, all-trans-retinoic acid, added just before heat shock, prevents the increase in mRNAs for collagenase and stromelysin. Our data suggest that heat shock may be an additional mechanism whereby collagenase and stromelysin are increased during rheumatoid arthritis and perhaps in other chronic inflammatory stress conditions.

scholarly journals Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA)

2008 ◽  
Vol 68 (9) ◽  
pp. 1486-1493 ◽  
Author(s):  
M F Roelofs ◽  
M H Wenink ◽  
F Brentano ◽  
S Abdollahi-Roodsaz ◽  
B Oppers-Walgreen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mrna Expression ◽  
Cytokine Production ◽  
Synovial Fibroblasts ◽  
Synovial Inflammation ◽  
Biologically Active ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Increased Risk

Background:Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA.Objectives:To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium.Methods:Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon α (IFNα), tumour necrosis factor α (TNFα) and interleukins IL1β, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1β, IL6 and TNFα were measured by Luminex bead array technology. Following preincubation with IFNα, IL1β and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNα and subsequent TLR stimulation was measured.Results:Synovial TLR3/7 expression was co-expressed with IFNα, IL1β and IL18, but not with TNFα, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1β or IL18 could be detected. Type I IFNα increased TLR3/7 mRNA expression whereas IL1β and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNα enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA.Conclusion:Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

scholarly journals Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Manuel J. Del Rey ◽  
Álvaro Valín ◽  
Alicia Usategui ◽  
Sandra Ergueta ◽  
Eduardo Martín ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Mrna Expression ◽  
Inflammatory Mediators ◽  
Synovial Fibroblasts ◽  
Initial Exposure ◽  
Inflammatory Phenotype ◽  
Expression Response ◽  
Synovial Tissues ◽  
Proteins Secretion

Abstract Background Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF). Results The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-β-gal(+) SF after 14 days in culture positively correlated with donor’s age. Initial exposure to H2O2 or TNFα enhanced SF senescence and increased mRNA expression of IL6, CXCL8, CCL2 and MMP3 and proteins secretion. Senescent SF show a heightened IL6, CXCL8 and MMP3 mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalized IL6, CXCL8 and CCL2 mRNA expression. Conclusions Accumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.

scholarly journals Computational Biology Approach for Deciphering Etiological Pathway of Polygenic Diseases: Rheumatoid Arthritis

2018 ◽  
Vol 6 (4) ◽  
pp. 332-338
Author(s):  
Rubin M. Tamrakar ◽  
Anushruti Sangami ◽  
Sunita Dangol ◽  
Pramod Aryal
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Γδ T Cells ◽  
Synovial Fibroblasts ◽  
Mendelian Inheritance ◽  
Permanent Disability ◽  
Inflammatory Stress ◽  
Downstream Signaling ◽  
Tnf Α ◽  
The Many

  Rheumatoid Arthritis (RA) (OMIM ID: 180300) is an inflammatory autoimmune disease caused by immune reaction against the proliferating synovial fibroblasts. Nonsuppurative proliferation of synoviocytes frequently progresses to destroy the articular cartilages and underlying bone, resulting in permanent disability. Using system biology approach, candidate genes obtained from OMIM (Online Mendelian Inheritance in Man) and its interacting proteins were prioritized on the basis of three Gene Ontology terms (Molecular Function, Cellular component, and Biological Process) employing FunSimMat (Functional Similarity Matrix). Among the many, four prioritized proteins NFκBIL1, HCST, MICA, and MICB were selected. Amongst the prioritized genes, literature review suggested that NFκBIL-1 (Nuclear Factor-κ of B-cell Inhibitor Like protein-1) (UniProtKB ID: Q9UBC1) competes against SR (Ser-Arg) protein, ASF/SF2, in negatively regulating CD45RO gene expression in CD4 T-cells, whose overproduction would lead to cytokine outburst, thus leading to an immunological attack. ASF/SF2 mediated splicing variant, CD45RA, otherwise would have prevented overproduction of these cytokines. Overproduced cytokines such as TNF-α, IL-6, IL-15 simultaneously induces inflammatory stress in the synovial membrane and activates stress induced MICA/B (UniProtKB ID: Q29983/Q29980) through downstream signaling following TNFR1-TRAF mediated signaling pathway. Synovial expression of MICA/B enables interaction with its ligand NKG2D associated with DAP10 (UniProt KB ID: Q9UBK5) amply present on CD8+ αβ T-cells, CD4+γδ T-cells, and NK cells, thus promoting cytolysis of MICA/B expressing synoviocytes along with further production of cytokines TNF-α and IL-15. Hence, alteration in NFκBIL-1 promoter induces MICA/B expression that leads in production of cytokines could be a probable cause of chronic RA. Int. J. Appl. Sci. Biotechnol. Vol 6(4): 332--338

The Role of Synovial Fibroblasts in Mediating Joint Destruction in Rheumatoid Arthritis

2005 ◽  
Vol 11 (5) ◽  
pp. 563-568 ◽  
Author(s):  
Ingmar Meinecke ◽  
Edita Rutkauskaite ◽  
Steffen Gay ◽  
Thomas Pap
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts

Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

2019 ◽  
Vol 13 (2) ◽  
pp. 140-148
Author(s):  
Mai Nasser ◽  
Noha M. Hazem ◽  
Amany Atwa ◽  
Amina Baiomy
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
Mrna Expression ◽  
Disease Activity Score ◽  
Activity Score ◽  
Tlr2 Expression ◽  
Positive Correlation ◽  
Tlr2 Mrna

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

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