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Regulation of TNF--induced IL-6 Production in MG-63 Human Osteoblast-like Cells

¹ Formerly Dept. of Oral Biology, UNMC, and presently Dept. of Orthodontics, The Ohio State University, Columbus, OH;
² formerly Dept. of Oral Biology, UNMC, and presently in private practice, Roseburg, OR;
³ Dept. of Oral Biology, UNMC, 40th & Holdrege Sts., Lincoln, NE 68583;

*corresponding author, skoka{at}unmc.edu

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

KEY WORDS: map kinase • interleukin-6 • osteoblast • inflammation

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