p70 S6 kinase limits tumor necrosis factor-α-induced interleukin-6 synthesis in osteoblast-like cells

Our previous study demonstrated that tumor necrosis factor-α (TNF-α) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p70 S6 kinase is involved in TNF-α-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-α time dependently induced the phosphorylation of p70 S6 kinase. Rapamycin, an inhibitor of p70 S6 kinase, which attenuated the phosphorylation of p70 S6 kinase induced by TNF-α, significantly amplified the TNF-α-stimulated IL-6 synthesis. TNF-α-induced phosphorylations of both p44/p42 MAP kinase and Akt were markedly enhanced by rapamycin. The amplification by rapamycin of TNF-α-induced IL-6 synthesis was reduced by PD98059, a specific inhibitor of MEK1/2, or Akt inhibitor. Rapamycin enhanced the IL-6 synthesis and the phosphorylation of Akt induced by TNF-α also in human osteoblasts. Taken together, these results strongly suggest that p70 S6 kinase limits the TNF-α-stimulated IL-6 synthesis at a point upstream from p44/p42 MAP kinase and Akt in osteoblast-like cells.