Interleukin-6 attenuates agonist-mediated calcium mobilization in murine osteoblastic cells.
Interleukin-6 (IL-6) is a multifunctional cytokine which is made by osteoblasts and has diverse effects on bone metabolism. We studied the interaction of IL-6 with the Ca2+ and cAMP signaling systems in the osteoblastic cell line UMR-106 and in primary osteoblastic cultures derived from neonatal rat calvariae. IL-6 did not alter basal intracellular calcium concentration ([Ca2+]i) but inhibited Ca2+ transients induced by parathyroid hormone (PTH), prostaglandin E2 (PGE2), and endothelin-1 in both dose- (100-400 U/ml) and time- (4-48 h) dependent manners. The effect of the cytokine was abolished by the tyrosine kinase inhibitor, herbimycin A (50 ng/ml). The IL-6 effect on the Ca2+ message system was related to suppressed production of hormonally induced inositol 1,4,5-triphosphate and inhibition of Ca2+ release from intracellular stores. Hormonally induced calcium entry pathways (estimated by using Mn2+ as a surrogate for Ca2+) were not, however, altered by the cytokine. IL-6 did not modulate cAMP generation in osteoblasts. With respect to osteoblast function, IL-6, although having no effect on cell proliferation by itself, greatly enhanced the antiproliferative effect of PGE2 and PTH. Because the production of IL-6 in osteoblasts is stimulated by calciotropic hormones (e.g., PTH and PGE2), the suppressive effect of the cytokine on hormonally induced Ca2+ transients may serve as an autocrine/paracrine mechanism for modulating the effect of hormones on bone metabolism.
Green
J
J
Laboratory of Membrane Biology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles 90048.
Schotland
S
S
Sella
Z
Z
Kleeman
C R
CR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D015850:Interleukin-6 / Q000494:pharmacology*; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D015220:Calcium Channels; D015850:Interleukin-6; D010281:Parathyroid Hormone; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium