Interleukin (IL)‐17 enhances tumor necrosis factor‐α‐stimulated IL‐6 synthesis via p38 mitogen‐activated protein kinase in osteoblasts

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Abstract
Inflammatory cytokines are well known to play crucial roles in the pathogenesis of rheumatoid arthritis. Among them, interleukin (IL)-17 is a cytokine that is mainly synthesized by activated T cells and its receptors are present in osteoblasts. The synthesis of IL-6, known to stimulate osteoclastic bone resorption, is reportedly responded to bone resorptive agents such as tumor necrosis factor-α (TNF-α) in osteoblasts. It has been reported that IL-17 enhances TNF-α-stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells. We previously showed that sphingosine 1-phosphate (S1-P) mediates TNF-α-stimulated IL-6 synthesis in these cells. In the present study, we investigated the mechanism of IL-17 underlying enhancement of IL-6 synthesis in MC3T3-E1 cells. IL-17 induced phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, significantly reduced the enhancement by IL-17 of TNF-α-stimulated IL-6 synthesis. IL-17 also amplified S1-P-stimulated IL-6 synthesis, and the amplification by IL-17 was suppressed by SB203580. Anisomycin, an activator of p38 MAP kinase, which alone had no effect on IL-6 level, enhanced the IL-6 synthesis stimulated by TNF-α. SB203580 and PD169316 inhibited the amplification by anisomycin of the TNF-α-induced IL-6 synthesis. Taken together, our results strongly suggest that IL-17 enhances TNF-α-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.