REGULATION OF INTERLEUKIN-6 PRODUCTION BY PROSTAGLANDIN E-2 IN FETAL-RAT OSTEOBLASTS - ROLE OF PROTEIN-KINASE-A SIGNALING PATHWAY

Prostaglandin E-2 (PGE(2)) is an abundant eicosanoid in bone that has been implicated in a number of pathological states associated with hon e loss. Interleukin-6 (IL-6) is a cytokine that plays a critical role in bone remodeling and appears to act as a downstream effector of most bone-resorbing agents. In light of the evidence that PGE(2) induces I L-6 in the bone environment, this study was designed to investigate wh ether PGE(2) regulated IL-6 expression by osteoblasts. Here we demonst rate that PGE(2) is a potent inducer of IL-6 production by fetal rat o steoblasts and synergizes with lipopolysaccharide to enhance IL-6. We show that PGE(2), stimulates the activity of the IL-6 promoter in oste oblasts, suggesting that PGE(2) controls IL-6 gene expression at least at the transcriptional level. Moreover, we show that PGE(2)-mediated IL-6 induction is prevented by the cAMP antagonist, Rp-cAMP, and the p rotein kinase A (PKA) inhibitors, KT5720 and H89. This, our data indic ate that PGE, involves the cAMP-PKA signaling pathway to regulate IL-6 gene expression in osteoblasts.