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

J Rheumatol. 1999 May;26(5):1035-43.


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-alpha (TNF-alpha) was measured by ELISA. Expression of CD40 on ST cells was quantified by anti-CD40 monoclonal antibodies and 125I 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-alpha in a dose dependent fashion. Adherent, but not non-adherent, fraction of ST cells responded to ligation of CD40 to produce TNF-alpha. Interferon-gamma (IFN-gamma), interleukin 4 (IL-4), or IL-13 acted synergistically with CD40 ligation to enhance TNF-alpha production by ST cells. IL-10 exerted inhibitory effects on both CD40 ligation induced and CD40 ligation plus IFN-gamma induced TNF-alpha 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-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.

MeSH terms

  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • CD40 Antigens* / metabolism
  • CD40 Ligand
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Humans
  • Interleukin-10 / metabolism
  • Lymphocyte Activation
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / metabolism*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism*


  • CD40 Antigens
  • Cytokines
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • CD40 Ligand