Interleukin‐10 functions as an antiinflammatory cytokine in rheumatoid synovium

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Abstract
Objective. Interleukin-10 (IL-10) is an antiinflammatory cytokine that has been shown to play a role in rheumatoid arthritis (RA). We therefore investigated the effects of IL-10 on the function and phenotype of synovial fluid mononuclear cells (SFMC) derived from patients with RA. In addition, we studied the production of IL-10 in rheumatoid joints, and the role of endogenous IL-10 in the regulation of SFMC function. Methods. The presence of IL-10 in rheumatoid joints was studied using IL-10–specific enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase–polymerase chain reaction (RT-PCR) techniques. The effects of recombinant human IL-10 or neutralizing anti–IL-10 monoclonal antibodies (MAbs) on both cytokine production and phenotype of SFMC were evaluated using cytokine-specific ELISAs and flow cytometry. The effect of IL-10 on proliferation of SFMC was determined by incorporation of tritiated thymidine. Results. IL-10 was detected by ELISA in 22 of 23 SF samples, and was spontaneously produced by cultured SFMC. IL-10 messenger RNA was detectable in all 8 SFMC samples, as determined by RT-PCR. Neutralization of endogenously produced IL-10 by anti–IL-10 MAbs resulted in increased production of IL-1β, tumor necrosis factor α (TNF α), and granulocyte–macrophage colony-stimulating factor (GM-CSF) by SFMC, and in enhanced proliferation of SFMC. In particular, the production of TNF α was dramatically increased by anti–IL-10 MAbs. Moreover, the expression of HLA–DR molecules by SF macrophages was increased, and the expression of CD16 was decreased by anti–IL-10 MAbs. In contrast, addition of recombinant IL-10 significantly decreased the production of IL-1β, TNF α, and GM-CSF by SFMC, and decreased spontaneous and IL-2–induced proliferation of SFMC. Finally, IL-10 decreased HLA–DR expression and increased the expression of the Fcγ receptors, CD16 and CD64, by SF macrophages. Conclusion. These data indicate that endogenously produced IL-10 functions as an immunoregulatory molecule in rheumatoid synovium. Importantly, exogenous IL-10 has potent antiinflammatory effects on SFMC, suggesting that IL-10 may be useful in the treatment of patients with RA.