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Il-4 and IL-13, but not IL-10, protect human synoviocytes from apoptosis

Relic, B.
Guicheux, J.
Lubberts, E.
Togninalli, D.
van den Berg, W. B.
Guerne, P. A.
Published in Journal of Immunology. 2001, vol. 166, no. 4, p. 2775-2782
Abstract Interleukin-4, which has been contemplated for the treatment of rheumatoid arthritis and/or osteoarthritis because of its anticatabolic properties, has also been shown to modulate apoptosis. Because inadequate apoptosis is thought to contribute to synovial hyperplasia, we have investigated the ability of IL-4 and other Th2 cytokines to protect human synovial cells from apoptosis. Human synoviocytes or synovial explants were pretreated with IL-4, IL-10, and IL-13 before exposure to NO donor sodium-nitro-prusside (SNP). Apoptosis was evaluated by microscopy, annexin V-FITC, 3-(4,5-dimethylthiazol-2-gl)-5-(3-carboxymethoxylphenyl)-2-(4-sulphophenyl-2H: tetrazolium inner salt (MTS) test, pulse field gel electrophoresis, and a method proposed in this study based on (32)P Klenow end labeling of high m.w. DNA. Pretreatment by IL-4 or IL-13, but not IL-10, protected human synoviocytes from apoptosis induced by SNP. Even at doses as high as 2 mM SNP, up to 86% and 56% protection was achieved, after IL-4 and IL-13 treatment, respectively. Cell survival was dependent on IL concentration. IL-4 and IL-13 also had antiapoptotic effects on SNP-treated human synovial explants. Effects of IL-4 and IL-13 varied in the presence of phosphatidylinositol-3 kinase and protein kinase C inhibitors, implying the involvement of these pathways in antiapoptotic signaling. Antiapoptotic effects were dramatically inhibited by LY294002, and partially by the protein kinase C inhibitor Go 6976, while insulin-like growth factor increased synoviocyte survival. The possibility that IL-4 and IL-13 may enhance synovial expansion in vivo by their antiapoptotic effects is discussed.
Keywords Adjuvants, Immunologic/pharmacologyApoptosis/drug effects/ immunologyArthritis, Rheumatoid/immunology/pathologyCarbazoles/pharmacologyChromones/pharmacologyCulture TechniquesDown-Regulation/drug effects/immunologyEnzyme Inhibitors/pharmacologyHumansImmunosuppressive Agents/pharmacologyIndoles/pharmacologyInsulin-Like Growth Factor I/pharmacologyInterleukin-10/ physiologyInterleukin-13/antagonists & inhibitors/ physiologyInterleukin-4/antagonists & inhibitors/ physiologyMorpholines/pharmacologyNitric Oxide/antagonists & inhibitors/pharmacologyNitric Oxide Donors/antagonists & inhibitors/pharmacologyNitroprusside/pharmacologyOsteoarthritis/immunology/pathologyProtein Kinase C/antagonists & inhibitorsSynovial Membrane/ cytology/drug effects/enzymology/ immunology
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