Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcomacells

Epinephrine increased gene- and protein-expression of interleukin-6 (IL-6) and interleukin-11 (IL-11), which are capable of stimulating the developmen t of osteoclasts from their hematopoietic precursors, in human osteoblast ( SaM-1) and human osteosarcoma (SaOS-2, HOS, and MG-63) cell lines. An incre ase in IL-6 and IL-11 synthesis in response to epinephrine appeared to be a common feature in osteoblastic cells, but the magnitude of expression was different in these cell lines. In HOS cells treated with epinephrine, incre ases of IL-6 and IL-11 synthesis were inhibited by timolol (a beta -blocker ), H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide; an inhibitor of protein kinase A (PKA)) and SB203580 [4-(4-fluorophenyl)-2-(4- methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; an inhibitor of p38 mitoge n-activated protein kinase (MAPK)], but not by phentolamine (an alpha -bloc ker), calphostin C [an inhibitor of protein kinase C (PKC)], or PD98059 (2' -amino-3'-methoxyflavone: an inhibitor of classic MAPK), suggesting a commo n pathway mediated by P-adrenergic receptors in the PKA and p38 systems inv olved in the signal transduction of IL-6 and IL-11. Furthermore, expression of both genes was inhibited by curcumin lan inhibitor of activating protei n-1 (AP-1) activation], but not by pyrrolidine dithiocarbamate (PDTC) [an i nhibitor of nuclear factor (NF)-kappaB]. The pharmacological study suggeste d that coinduction of the two genes in response to epinephrine occurred via activation of AP-1. The findings of the present study suggest that coinduc tion of IL-6 and IL-11 in response to epinephrine probably occurs via the P KA and p38 MAPK systems. leading to the transcriptional activation of AP-1 in human osteoblastic cells. (C) 2001 Elsevier Science Inc. All rights rese rved.