OBJECTIVE: The inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL-10 is a potent antiinflammatory cytokine that suppresses macrophage TNFalpha and IL-1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL-10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL-10-inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages. METHODS: Macrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL-10 or interferon-gamma (IFNgamma). Gene expression was analyzed using Affymetrix microarrays and protocols. Real-time polymerase chain reaction was used to confirm changes in gene expression. RESULTS: The number of genes induced by IL-10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL-10 stimulation was qualitatively altered, such that IL-10 preferentially increased expression of IFNgamma-inducible genes. In contrast, arthritic macrophages expressed many IFNgamma-inducible genes prior to stimulation, and their response to IFNgamma remained mostly intact. CONCLUSION: These results demonstrate that IL-10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL-10, with attenuation of its antiinflammatory function and a concomitant retention of IFNgamma-like activating functions, provides a basis for the lack of efficacy of IL-10 in suppressing inflammatory arthritis.
OBJECTIVE: The inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL-10 is a potent antiinflammatory cytokine that suppresses macrophage TNFalpha and IL-1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL-10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL-10-inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages. METHODS: Macrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL-10 or interferon-gamma (IFNgamma). Gene expression was analyzed using Affymetrix microarrays and protocols. Real-time polymerase chain reaction was used to confirm changes in gene expression. RESULTS: The number of genes induced by IL-10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL-10 stimulation was qualitatively altered, such that IL-10 preferentially increased expression of IFNgamma-inducible genes. In contrast, arthritic macrophages expressed many IFNgamma-inducible genes prior to stimulation, and their response to IFNgamma remained mostly intact. CONCLUSION: These results demonstrate that IL-10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL-10, with attenuation of its antiinflammatory function and a concomitant retention of IFNgamma-like activating functions, provides a basis for the lack of efficacy of IL-10 in suppressing inflammatory arthritis.
Authors: Priya Darshinee A Issuree; Thorsten Maretzky; David R McIlwain; Sébastien Monette; Xiaoping Qing; Philipp A Lang; Steven L Swendeman; Kyung-Hyun Park-Min; Nikolaus Binder; George D Kalliolias; Anna Yarilina; Keisuke Horiuchi; Lionel B Ivashkiv; Tak W Mak; Jane E Salmon; Carl P Blobel Journal: J Clin Invest Date: 2013-01-25 Impact factor: 14.808