EFFECTS OF SK-AND-F-86002 ON CYTOKINE-STIMULATED IL6 PRODUCTION IN CULTURED NEONATAL MOUSE CALVARIA AND SAOS2 OSTEOBLASTIC CELLS - THE ROLEOF PROSTAGLANDINS AND OTHER MECHANISMS OF ACTION

The cytokine-suppressant anti-inflammatory drug (CSAID) SK&F 86002 inh ibits bone resorption in vitro and this effect cannot be totally expla ined by its inhibition of lL1 beta and TNF alpha release. IL6 is anoth er cytokine important in the mechanisms of bone resorption and could b e a target for the actions of SK&F 86002. IL6 release and resorption ( Ca-45 release) were induced by IL1 beta in neonatal mouse calvaria bon es in culture. Both indomethacin (5 x 10(-8)-5 x 10(-6)M) and SK&F 860 02 (5 x 10(-7)-10(-5)M) markedly inhibited the IL6 release and totally inhibited resorption at all concentrations tested. This may result fr om inhibition of prostaglandin production by both compounds. In human osteoblastic cells (SaOS2) both basal and TNF alpha-stimulated IL6 pro duction were inhibited in a concentration-related manner by SK&F 86002 but not by indomethacin. The effect of SK&F 86002 was greatest in 6h cultures where relatively low levels of IL6 are produced and progressi vely less in 24 and 48h cultures which produce higher levels of IL6. T his is unlikely to be an indirect effect via inhibition of IL1 beta pr oduction as no IL1 beta (<0.3 pg/ml) was detected in non-stimulated or stimulated culture supernatants. Therefore, SK&F 86002,nay inhibit IL 6 production in osteoblastic cells via a more direct mechanism, possib ly involving inhibition of the p38 MAP kinase, the mechanism proposed for its inhibition of IL1 beta and TNF alpha release.