Effects of SK&F 86002 on cytokine-stimulated IL6 production in cultured neonatal mouse calvaria and SaOS2 osteoblastic cells: the role of prostaglandins and other mechanisms of action.

The cytokine-suppressant anti-inflammatory drug (CSAID) SK&F 86002 inhibits bone resorption in vitro and this effect cannot be totally explained by its inhibition of IL 1β and TNFα release. IL6 is another cytokine important in the mechanisms of bone resorption and could be a target for the actions of SK&F 86002. IL6 release and resorption ( 45 Ca release) were induced by IL 1β in neonatal mouse calvaria bones in culture. Both indomethacin (5x10 -8 -5x10 -6 M) and SK&F 86002 (5x10 -7 -10 -5 M) markedly inhibited the IL6 release and totally inhibited resorption at all concentrations tested. This may result from inhibition of prostaglandin production by both compounds. In human osteoblastic cells (SaOS2) both basal and TNFα-stimulated IL6 production 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 progressively less in 24 and 48h cultures which produce higher levels of IL6, This is unlikely to be an indirect effect via inhibition of IL 1β production as no IL 1β (<0.3pg/ml) was detected in non-stimulated or stimulated culture supernatants. Therefore, SK&F 86002 may inhibit IL6 production in osteoblastic cells via a more direct mechanism, possibly involving inhibition of the p38 MAP kinase, the mechanism proposed for its inhibition of IL 1β and TNFα release.