Il-4 and IL-13, but not IL-10, protect human synoviocytes from apoptosis.
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 Gö 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.
Relic
B
B
Division of Rheumatology and Department of Orthopedic Surgery, University Hospital, Geneva, Switzerland.
Guicheux
J
J
Mezin
F
F
Lubberts
E
E
Togninalli
D
D
Garcia
I
I
van den Berg
W B
WB
Guerne
P A
PA
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D046508:Culture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D000276:Adjuvants, Immunologic; D002227:Carbazoles; D002867:Chromones; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007211:Indoles; D018793:Interleukin-13; D009025:Morpholines; D020030:Nitric Oxide Donors; D016753:Interleukin-10; C081021:Go 6976; D009599:Nitroprusside; D015847:Interleukin-4; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C