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      A proinflammatory role for IL-18 in rheumatoid arthritis.

      The Journal of clinical investigation

      Transcription, Genetic, immunology, Th1 Cells, pathology, Synovial Membrane, chemistry, Synovial Fluid, Receptors, Interleukin-18, genetics, analysis, Receptors, Interleukin, RNA, Messenger, Protein Biosynthesis, physiopathology, Osteoarthritis, Mice, Inbred DBA, Mice, Macrophages, Interleukin-18 Receptor alpha Subunit, physiology, Interleukin-18, pharmacology, Interleukin-15, Interleukin-12, Interferon-gamma, Inflammation, Humans, Gene Expression Regulation, Enzyme-Linked Immunosorbent Assay, Cell Line, Arthritis, Rheumatoid, Arthritis, Experimental, Antigens, CD3, Animals, Tumor Necrosis Factor-alpha

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          Abstract

          IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.

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          Author and article information

          Journal
          409841
          10.1172/JCI7317
          10562301

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