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 ligand (CD40L) interaction in rheumatoid arthritis (RA). Methods. The expression of CD40 ligand (CD40L) in synovial tissues (ST) from patients with RA was examined by immunohistochemistry. Tumor necrosis factor-α (TNF-α) was measured by ELISA. Expression of CD40 on ST cells was quantified by anti-CD40 monoclonal antibodies and 125 I labelled anti-mouse IgG. Results. Immunohistochemistry showed CD40L+ T cells in RA ST. Ligation of CD40 on RA ST cells significantly increased the production of TNF-α in a dose dependent fashion. Adherent, but not non-adherent, fraction of ST cells responded to ligation of CD40 to produce TNF-α. Interferon-γ (IFN-γ), interleukin 4 (IL-4), or IL-13 acted synergistically with CD40 ligation to enhance TNF-α production by ST cells. IL-10 exerted inhibitory effects on both CD40 ligation induced and CD40 ligation plus IFN-γ induced TNF-α production by ST cells. Conclusion. These data indicate activated T cells participate in synovial inflammation of RA via CD40L to stimulate the production of TNF-α by ST cells. The effect of CD40 ligation is modulated by the presence of several cytokines, e.g., IFN-γ, IL-4, IL-10, and IL-13.