Regulation of TNF-alpha-induced IL-6 production in MG-63 human osteoblast-like cells

J Dent Res. 2002 Jan;81(1):17-22. doi: 10.1177/002203450208100105.


Tumor necrosis factor-alpha (TNF-alpha) stimulates osteoblast production of interleukin-6 (IL-6), an inflammatory cytokine implicated in osteoclastic bone resorption. Therefore, we tested the hypothesis that TNF-alpha-induced IL-6 production in MG-63 osteosarcoma cells occurs via the p38 mitogen-activated protein kinase (MAPK) pathway. TNF-alpha activated p38 MAPK and stimulated IL-6 secretion by MG-63 cells, and pre-incubation of cells with the p38 MAPK inhibitor abrogated TNF-alpha-dependent IL-6 secretion. Transfection of IL-6 full-length and 5-deletion gene promoter reporter constructs indicated that p38 MAPK activation by TNF-alpha enhanced IL-6 gene expression, and that the p38 MAPK-responsive region resided in the proximal 260-bp segment. Transfection of NFkappaB and C/EBPbeta-sensitive reporter promoter constructs demonstrated that NFkappaB activity was enhanced and that constitutive C/EBPbeta was inhibited by TNF-alpha, with both effects being p38 MAPK-dependent. In conclusion, although p38 MAPK activation by TNF-alpha stimulates IL-6 secretion by MG-63 cells, it has opposing effects on c/EBPbeta and NFkappaB activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • CCAAT-Enhancer-Binding Protein-beta / physiology
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / physiology
  • Osteoblasts / drug effects*
  • Osteoblasts / enzymology
  • Osteoblasts / metabolism*
  • Osteosarcoma
  • Promoter Regions, Genetic
  • Statistics, Nonparametric
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / physiology
  • p38 Mitogen-Activated Protein Kinases


  • CCAAT-Enhancer-Binding Protein-beta
  • Interleukin-6
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases