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Predominant activation of MAP kinases and pro- destructive/pro-inflammatory features by TNF-alpha in early-passage, rheumatoid arthritis and osteoarthritis synovial fibroblasts via tumor necrosis factor receptor- 1: Failure of p38 inhibition to suppress matrix metalloproteinase-1 in rheumatoid arthritis
  1. Elke Kunisch
  1. Experimental Rheumatology Unit, Department of Orthopedics, Friedrich Schiller University, Germany
    1. Mukteshwar Gandesiri
    1. Experimental Rheumatology Unit, Department of Orthopedics, Friedrich Schiller University, Germany
      1. Reneé Fuhrmann
      1. Clinic of Orthopedics, Friedrich Schiller University Jena, Germany
        1. Andreas Roth
        1. Clinic of Orthopedics, Friedrich Schiller University Jena, Germany
          1. Rando Winter
          1. Clinic of Orthopedics, Friedrich Schiller University Jena, Germany
            1. Raimund W Kinne (raimund.w.kinne{at}rz.uni-jena.de)
            1. Clinical Research Unit Rheum/Immunology, Germany

              Abstract

              Objective: To address the relative importance of tumor necrosis factor-receptor 1 (TNF-R1)/TNF-R2 and their signaling pathways for pro-inflammatory and pro- destructive features of early-passage synovial fibroblasts (SFB) from rheumatoid arthritis (RA) and osteoarthritis (OA).

              Methods: Cells were stimulated with TNF-alpha or agonistic anti-TNF-R1/TNF-R2 mAbs. Phosphorylation of p38, ERK, and JNK kinases was assessed by western blot; proliferation by bromodesoxyuridine incorporation; IL-6, IL-8, PGE2, and MMP-1 secretion by ELISA and MMP-3 secretion by western-blot. Functional assays were performed with/without inhibition of p38 (SB203580), ERK (U0126), or JNK (SP600125).

              Results: In RA- and OA-SFB, TNF-alpha-induced phosphorylation of p38, ERK, or JNK was exclusively mediated via TNF-R1. Reduction of proliferation and induction of IL-6, IL-8, and MMP-1 were solely mediated by TNF-R1, whereas PGE2 and MMP-3 secretion was mediated by both TNF-Rs. In general, inhibition of ERK or JNK did not significantly alter the TNF-alpha influence on these effector molecules. In contrast, inhibition of p38 reversed TNF-alpha effects on proliferation and IL- 6/PGE2 secretion (but not on IL-8 and MMP-3 secretion). The above effects were comparable in RA- and OA-SFB, except that TNF-alpha-induced MMP-1 secretion was reversed by p38 inhibition only in OA-SFB.

              Conclusion: In early-passage RA/OA-SFB, activation of MAPK cascades and pro-inflammatory/pro- destructive features by TNF-alpha is predominantly mediated by TNF-R1 and, for proliferation and IL-6/PGE2, exclusively regulated by p38. Strikingly, RA-SFB are insensitive to p38 inhibition of MMP-1 secretion. This indicates a resistance of RA-SFB to the inhibition of pro-destructive functions and suggests underlying structural/functional alterations of the p38 pathway, which may contribute to the pathogenesis and/or therapeutic sensitivity of RA.

              • MMP
              • TNF-receptor
              • interleukin
              • p38 MAP kinase
              • synovial fibroblast

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