IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis.
T lymphocytes are a major component of the inflammatory infiltrate in rheumatoid synovitis, but their exact role in the disease process is not understood. Functional activities of synovial T cells were examined by adoptive transfer experiments in human synovium-SCID mouse chimeras. Adoptive transfer of tissue-derived autologous CD8+ T cells induced a marked reduction in the activity of lesional T cells and macrophages. Injection of CD8+, but not CD4+, T cells decreased the production of tissue IFN-gamma, IL-1beta, and TNF-alpha by >90%. The down-regulatory effect of adoptively transferred CD8+ T cells was not associated with depletion of synovial CD3+ T cells or synovial CD68+ macrophages, and it could be blocked by Abs against IL-16, a CD8+ T cell-derived cytokine. In the synovial tissue, CD8+ T cells were the major source of IL-16, a natural ligand of the CD4 molecule that can anergize CD4-expressing cells. The anti-inflammatory activity of IL-16 in rheumatoid synovitis was confirmed by treating synovium-SCID mouse chimeras with IL-16. Therapy for 14 days with recombinant human IL-16 significantly inhibited the production of IFN-gamma, IL-1beta, and TNF-alpha in the synovium. We propose that tissue-infiltrating CD8+ T cells in rheumatoid synovitis have anti-inflammatory activity that is at least partially mediated by the release of IL-16. Spontaneous production of IL-16 in synovial lesions impairs the functional activity of CD4+ T cells but is insufficient to completely abrogate their stimulation. Supplemental therapy with IL-16 may be a novel and effective treatment for rheumatoid arthritis.
Klimiuk
P A
PA
Department of Medicine, Division of Rheumatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Goronzy
J J
JJ
Weyand
C M
CM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007274:Injections, Intraperitoneal; D019410:Interleukin-16 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000276:immunology* / Q000473:pathology / Q000628:therapy
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019410:Interleukin-16