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THU0091 Il-8 production induced by protein i/ii, a modulin from oral streptococci, in synoviocytes from rheumatoid arthritis (ra) patients involves the mapks and fak signalling pathways and nf-kb
  1. L Neff1,
  2. M Zeisel1,
  3. FX Limbach2,
  4. JP Klein1,
  5. D Wachsmann1,
  6. J Sibilia2
  1. 1Pharmacology
  2. 2Rheumatology, CHU Hautepierre, Strasbourg, France

Abstract

Background Protein I/II, an adhesin from viridans streptococci, commensal bacteria of the oral cavity, can stimulate different cells including endothelial cells. After binding to its receptor, integrin Α5Β1, protein I/II promotes release of IL-6 and IL-8 from endothelial cells, which contributes to the recruitment of circulating leukocytes from the blood into tissues. IL-8 has recently by associated with the pathogenesis of various chronic inflammatory disorders such as RA. IL-8 could be produced in response to commensal bacteria which could disseminate through bacteremia.

Objectives To study the interactions of protein I/II with fibroblast-like synoviocytes from RA patients.

Results

  • Protein I/II increased the IL-8 synthesis of fibroblast-like synoviocytes through transcriptional up-regulation of the IL-8 gene (ELISA and RT-PCR).

  • IL-8 synthesis was inhibited by the tyrosine kinase inhibitor herbimycin A and by inhibitors of MAPKs such as apigenin and PD 98059, while focal adhesion kinase (FAK) and ERK1/2 phosphorylation was increased by Protein I/II.

  • Protein I/II increased activated nuclear translocation of the transcription factor NF-ΚB (EMSA with an NF-ΚB specific probe). This was confirmed by inhibition with curcumin, an inhibitor of NF-ΚB, which blocked IL-8 release from protein I/II-activated synoviocytes.

Conclusion

  • After binding to synoviocytes, protein I/II induces IL-8 release by activaing the FAK and MAPKs signalling pathways.

  • The transcription factor NF-ΚB plays a major role in the up-regulation of IL-8 synthesis and release mediated by NF-ΚB.

  • Synoviocytes activation could be triggered by commensal bacteria, which could spread to the joints through bacteremia in RA and others forms of arthritis.

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