Abstract
An excess of the proinflammatory substance IL-18 is present in joints of patients with rheumatoid arthritis (RA), and expression of IL-18 receptor (IL-18R) regulates IL-18 bioactivity in various cell types. We examined the expression of IL-18R alpha-chain and beta-chain and the biologic effects of IL-18 in fibroblast-like synoviocytes (FLS) after long-term culture. The presence of both IL-18R chains was a prerequisite for IL-18 signal transduction in FLS. However, all FLS cultures studied were either resistant or barely responsive to IL-18 stimulation as regards cell proliferation, expression of adhesion molecules ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and the release of interstitial collagenase and stromelysin, IL-6 and IL-8, prostaglandin E2, or nitric oxide. We conclude that the presence of macrophages or IL-18R+ T cells that can respond directly to IL-18 is essential for the proinflammatory effects of IL-18 in synovitis in RA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism
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Cell Division / drug effects
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Cells, Cultured
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Collagenases / metabolism
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Culture Media, Conditioned / metabolism
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Dinoprostone / metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Humans
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Intercellular Adhesion Molecule-1 / metabolism
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Interleukin-18 / metabolism
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Interleukin-18 / pharmacology
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Interleukin-18 Receptor alpha Subunit
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Interleukin-6 / metabolism
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Interleukin-8 / metabolism
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Matrix Metalloproteinase 3 / metabolism
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Nitric Oxide / metabolism
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RNA, Messenger / metabolism
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Receptors, Interleukin / genetics
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Receptors, Interleukin / metabolism*
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Receptors, Interleukin-18
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Signal Transduction
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Synovial Membrane / drug effects
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Synovial Membrane / metabolism*
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Synovial Membrane / pathology
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U937 Cells / drug effects
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U937 Cells / metabolism
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U937 Cells / pathology
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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Culture Media, Conditioned
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IL18R1 protein, human
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Interleukin-18
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Interleukin-18 Receptor alpha Subunit
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Interleukin-6
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Interleukin-8
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-18
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Nitric Oxide
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Collagenases
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Matrix Metalloproteinase 3
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Dinoprostone