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Open Access

Resistance of rheumatoid arthritis synovial fibroblasts to p38 MAP-kinase inhibition of pro-destructive functions mediated by tumor necrosis factor alpha/tumor necrosis factor receptor-1

  • E Kunisch1,
  • B Ukena1,
  • R Fuhrmann2,
  • A Roth2,
  • R Winter2 and
  • RW Kinne1
Arthritis Research & Therapy20057(Suppl 1):P115

https://doi.org/10.1186/ar1636

Received: 11 January 2005

Published: 17 February 2005

Keywords

Rheumatoid ArthritisTumor Necrosis FactorOsteoarthritisPGE2SB203580

Objectives

In rheumatoid arthritis (RA), tumor necrosis factor (TNF) alpha is a major inductor of the proinflammatory/pro-destructive functions of synovial fibroblasts (SFB). These effects are predominantly mediated via the TNF receptor-1 (TNFR1). In addition to the NF-κB pathway, the p38 MAP kinase seems to play a central role for the underlying signal transduction. In the present study, RA-SFB were compared with osteoarthritis (OA)-SFB concerning the TNF-α/TNFR1/2-induced secretion of IL-6, IL-8, prostaglandin E2 (PGE2), and matrix metalloproteinase-1/tissue inhibitor of matrix metalloproteinase-1 (MMP-1/TIMP-1), as well as the sensitivity to p38 MAP-kinase inhibition.

Methods

Early-passage (second) RA-SFB and OA-SFB were analyzed for TNFR expression by FACS. The cells were then stimulated with TNF-α (10 ng/ml) or agonistic anti-TNFR1 (HTR-9) or anti-TNFR2 monoclonal antibodies (UTR-1; 10 μg/ml each) with/without inhibition of the p38 kinase by SB203580 (1 μM). Secretion of IL-6, IL-8, PGE2, MMP-1, and TIMP-1 was analyzed by ELISA.

Results

RA-SFB and OA-SFB both expressed TNFR1 and TNFR2 on their surface, without significant differences between the two groups. Secretion of IL-6, IL-8, PGE2, and MMP-1, but not TIMP-1, was significantly augmented by stimulation of RA-SFB and OA-SFB with TNF-α. Except for PGE2 (induced via both TNFRs), these effects were exclusively mediated via the TNFR1. Inhibition of p38 kinase reduced the secretion of IL-6 and PGE2 significantly and equally well in RA-SFB and OA-SFB. However, the secretion of MMP-1 was significantly suppressed only in OA-SFB, whereas RA-SFB were insensitive to the inhibition of MMP-1 secretion by p38 inhibition.

Conclusion

In early-passage RA-SFB and OA-SFB, TNF-α-induced proinflammatory/pro-destructive functions are predominantly mediated by TNFR1. Strikingly, RA-SFB are partially resistant to the suppression of pro-destructive MMP-1 by p38 MAP-kinase inhibition. The underlying structural or functional alterations of the p38 MAP kinase in RA-SFB may contribute to the pathogenesis and/or therapeutic sensitivity of RA.

Declarations

Acknowledgements

This study was supported by the German Federal Ministry of Education and Research (BMBF; grant FKZ 01ZZ0105 to RWK, Interdisciplinary Center for Clinical Research Jena) and the German Research Foundation (DFG; grant KI 439/7-1 to RWK), as well as a grant for the advancement of female scientists to EK (LUBOM Thuringia).

Authors’ Affiliations

(1)
Experimental Rheumatology Unit, Friedrich Schiller University Jena, Germany
(2)
Clinic of Orthopedics, Friedrich Schiller University Jena, Germany

Copyright

© BioMed Central Ltd 2005

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