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

Biochem Pharmacol. 2001 Feb 1;61(3):319-26. doi: 10.1016/s0006-2952(00)00544-x.


Epinephrine increased gene- and protein-expression of interleukin-6 (IL-6) and interleukin-11 (IL-11), which are capable of stimulating the development of osteoclasts from their hematopoietic precursors, in human osteoblast (SaM-1) and human osteosarcoma (SaOS-2, HOS, and MG-63) cell lines. An increase 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, increases 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 mitogen-activated protein kinase (MAPK)], but not by phentolamine (an alpha-blocker), calphostin C [an inhibitor of protein kinase C (PKC)], or PD98059 (2'-amino-3'-methoxyflavone; an inhibitor of classic MAPK), suggesting a common pathway mediated by beta-adrenergic receptors in the PKA and p38 systems involved in the signal transduction of IL-6 and IL-11. Furthermore, expression of both genes was inhibited by curcumin [an inhibitor of activating protein-1 (AP-1) activation], but not by pyrrolidine dithiocarbamate (PDTC) [an inhibitor of nuclear factor (NF)-kappaB]. The pharmacological study suggested that coinduction of the two genes in response to epinephrine occurred via activation of AP-1. The findings of the present study suggest that coinduction of IL-6 and IL-11 in response to epinephrine probably occurs via the PKA and p38 MAPK systems, leading to the transcriptional activation of AP-1 in human osteoblastic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agonists / pharmacology*
  • Adrenergic alpha-Antagonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Antioxidants / pharmacology
  • Curcumin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Epinephrine / pharmacology*
  • Gene Expression / drug effects
  • Humans
  • Interleukin-11 / biosynthesis*
  • Interleukin-6 / biosynthesis*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • NF-kappa B / antagonists & inhibitors
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Protein Kinase C / antagonists & inhibitors
  • Pyrrolidines / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction* / drug effects
  • Thiocarbamates / pharmacology
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Tumor Cells, Cultured


  • Adrenergic Agonists
  • Adrenergic alpha-Antagonists
  • Adrenergic beta-Antagonists
  • Antioxidants
  • Enzyme Inhibitors
  • Interleukin-11
  • Interleukin-6
  • NF-kappa B
  • Pyrrolidines
  • RNA, Messenger
  • Thiocarbamates
  • Transcription Factor AP-1
  • pyrrolidine dithiocarbamic acid
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Curcumin
  • Epinephrine