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 1 beta and TNF alpha 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 (45Ca release) were induced by IL 1 beta in neonatal mouse calvaria bones in culture. Both indomethacin (5 x 10(-8)-5 x 10(-6) M) and SK&F 86002 (5 x 10(-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 TNF alpha-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 6 h cultures where relatively low levels of IL6 are produced and progressively less in 24 and 48 h cultures which produce higher levels of IL6. This is unlikely to be an indirect effect via inhibition of IL 1 beta production as no IL 1 beta (< 0.3 pg/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 1 beta and TNF alpha release.
Blanque
R
R
Centre de Recherche Roussel-UCLAF, Romainville, France.
Cottereaux
C
C
Gardner
C R
CR
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D012886:Skull / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D011453:Prostaglandins; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D007213:Indomethacin