Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: A novel mechanism of activation of synoviocytes

Objective. To determine the immunopathological significance of CD40/CD40 li gand (CD40L) interaction in rheumatoid arthritis (RA). Methods. The expression of CD40 ligand (CD40L) in synovial tissues (ST) fro m patients with RA was examined by immunohistochemistry. Tumor necrosis fac tor-alpha (TNF-alpha) was measured by ELISA. Expression of CD40 on ST cells was quantified by anti-CD40 monoclonal antibodies and I-125 labelled anti- mouse IgG. Results, Immunohistochemistry showed CD40L+ T cells in RA ST. Ligation of C D40 on RA ST cells significantly increased the production of TNF-alpha in a dose dependent fashion. Adherent, but not non-adherent, fraction of ST cel ls responded to ligation of CD40 to produce TNF-alpha. Interferon-gamma (IF N-gamma), interleukin 4 (IL-4), or IL-13 acted synergistically with CD40 Li gation to enhance TNF-alpha production by ST cells. IL-10 exerted inhibitor y effects on both CD40 ligation induced and CD40 ligation plus IFN-gamma in duced TNF-alpha production by ST cells. Conclusion. These data indicate activated T cells participate in synovial i nflammation of RA via CD40L to stimulate the production of TNF-alpha by ST cells, The effect of CD40 ligation is modulated by the presence of several cytokines, e.g., IFN-gamma, IL-4, IL-10, and IL-13.