Phosphatidylinositol 3-Kinase/Akt Plays a Part in Tumor Necrosis Factor-α-induced Interleukin-6 Synthesis in Osteoblasts

Abstract

We previously showed that tumor necrosis factor-α (TNF-α) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (Akt) is involved in TNF-α-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-α induced the phosphorylation of Akt depending upon time. Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, significantly suppressed the TNF-α-stimulated IL-6 synthesis, but the inhibitory effect was partial. The phosphorylation of Akt induced by TNF-α was markedly attenuated by LY294002 and wortmannin, inhibitors of PI3-kinase. Wortmannin and LY294002 significantly reduce the TNF-α-induced IL-6 synthesis. On the contrary, the suppressive effects of Akt inhibitor, wortmannin or LY294002 on TNF-α-induced phosphorylation of p44/p42 MAP kinase were minor. PD98059, a specific inhibitor of MEK, had little effect on the TNF-α-induced phosphorylation of Akt. A combination of Akt inhibitor and PD98059 suppressed the TNF-α-induced IL-6 synthesis in an additive manner. These results strongly suggest that PI3-kinase/Akt plays a role in the TNF-α-stimulated IL-6 synthesis mainly independent of p44/p42 MAP kinase in osteoblasts.

Key words

TNF-α - IL-6 - Akt - phosphatidylinositol 3-kinase - osteoblast

References

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