Interleukin-1 β induces cyclic AMP formation in isolated human osteoblasts: a signalling mechanism that is not related to enhanced prostaglandin formation

Abstract

Interleukin-1 (IL-1) is a potent stimulator of bone resorption. Induction of osteoclastic bone resorption by various endocrine or paracrine factors is mediated via the osteoblasts. We have therefore investigated the effects of 1L-1 β on cell signalling in isolated human osteoblasts. Special interest was focused on prostaglandin synthesis, since indomethacin, an inhibitor of prostaglandin synthesis, partly inhibits IL-1-induced bone resorption. IL-1 β, at and above 0.3 pM, dose dependently stimulated PGE 2 formation in isolated human osteoblasts, with half maximal stimulation, EC 50, at 3 pM. Treatment with the calcium ionophore A23187 (1 μM), or with forskolin (30 μM), also stimulated PGE 2 formation in human osteoblasts. The time-course for IL-1 β-induced PGE 2 formation was similar to that of forskolin, with a significant increase in the formation of PGE 2 seen after 1 h. In contrast, A23187-induced PGE 2 formation was seen within minutes. IL-1 β stimulated the accumulation of cyclic AMP in isolated human osteoblasts incubated for 15 min. This increase in cyclic AMP formation was not secondary to PGE 2 formation since it was not blocked by the addition of indomethacin (1 μM). Pretreatment with the phosphodiesterase inhibitor IBMX did not augment IL-l β-induced PGE 2 formation, nor did the protein kinase A inhibitor Rp-cAMPs inhibit IL-1 β-induced PGE 2 formation, suggesting that cyclic AMP does not mediate the stimulatory effect of IL-1 on PGE 2 formation. We conclude that IL-1 β enhances the formation of cyclic AMP as well as PGE 2 in primary cultures of isolated human osteoblasts.The IL-1 β-induced cyclic AMP formation is, however, not related to the enhanced prostaglandin formation. The findings implicate that both cyclic AMP- and PGE 2-formation in osteoblasts might be involved as independent mediators of IL-1 β-induced bone resorption.