Regulation of interleukin-6 production by prostaglandin E2 in fetal rat osteoblasts: role of protein kinase A signaling pathway.
Prostaglandin E2 (PGE2) is an abundant eicosanoid in bone that has been implicated in a number of pathological states associated with bone 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 PGE2 induces IL-6 in the bone environment, this study was designed to investigate whether PGE2 regulated IL-6 expression by osteoblasts. Here we demonstrate that PGE2 is a potent inducer of IL-6 production by fetal rat osteoblasts and synergizes with lipopolysaccharide to enhance IL-6. We show that PGE2 stimulates the activity of the IL-6 promoter in osteoblasts, suggesting that PGE2 controls IL-6 gene expression at least at the transcriptional level. Moreover, we show that PGE2-mediated IL-6 induction is prevented by the cAMP antagonist, Rp-cAMP, and the protein kinase A (PKA) inhibitors, KT5720 and H89. Thus, our data indicate that PGE2 involves the cAMP-PKA signaling pathway to regulate IL-6 gene expression in osteoblasts.
Millet
I
I
Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut, USA.
McCarthy
T L
TL
Vignery
A
A
D000818:Animals; D002227:Carbazoles; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013873:Thionucleotides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D015850:Interleukin-6; D007546:Isoquinolines; D011758:Pyrroles; D013449:Sulfonamides; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide