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 anti-catabolic properties, h as also been shown to modulate apoptosis, Because inadequate apoptosis is t hought to contribute to synovial hyperplasia, we have investigated the abil ity of IL-4 and other Th2 cytokines to protect human synovial cells from ap optosis, 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 dimethylthiaz ol-2-gl)-5-(3-carboxy-methoxylphenyl)-2-(4-sulphophenyl-2H tetrazolium inne r salt (MTS) test, pulse held gel electrophoresis, and a method proposed in this study based on P-32 Klenow end labeling of high m,w, DNA, Pretreatmen t by IL-4 or IL-13, but not IL-10, protected human synoviocytes from apopto sis induced by SNP, Even at doses as high as 2 mM SNP, up to 86% and 56% pr otection was achieved, after IL-4 and IL-13 treatment, respectively. Cell s urvival,vas dependent on IL concentration. IL-4 and IL-13 also had anti-apo ptotic effects on SNP-treated human synovial explants, Effects of IL-4 and IL-13 varied in the presence of phosphatidylinositol-3 kinase and protein k inase C inhibitors, implying the involvement of these pathways in antiapopt otic signaling. Antiapoptotic effects were dramatically inhibited by LY2940 02, 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 e ffects is discussed.