Interleukin-10 inhibits RANKL-mediated expression of NFATc1 in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells

Saad Gad-Kamel Mohamed, Eiji Sugiyama, Kouichiro Shinoda, Hirofumi Taki, Hiroyuki Hounoki, Hekmat Osman Abdel-Aziz, Muneharu Maruyama, Masashi Kobayashi, Hirofumi Ogawa, Tatsuro Miyahara
Bone 2007, 41 (4): 592-602
Interleukin-10 (IL-10), an anti-inflammatory cytokine, has been shown to inhibit osteoclast formation and bone resorption in rat and mouse systems. However, the precise intracellular mechanism(s) of this action remains unclear. The aim of this study was to clarify the role of IL-10 in the regulation of critical transcription factors involved in osteoclastogenesis. A RAW264.7 macrophage cell line, which constitutively expressed IL-10 receptor, was differentiated to osteoclasts with stimulation of receptor activator of nuclear factor kappaB ligand (RANKL). IL-10 inhibited the RANKL-induced osteoclastogenesis. IL-10 potently reduced the RANKL-induced expression of NFATc1, c-Jun and c-Fos, which are known to be essential for osteoclastogenesis, in time- and dose-dependent manners. The IL-10-induced inhibition of these transcription factors was observed in the system of mouse bone marrow precursors. Besides these transcription factors, IL-10 also decreased the RANKL-induced expression of NF-kappaB p50 and phosphorylation of JNK. To determine which signaling was critical for the IL-10 effect, we examined the effect of overexpression of NFATc1, c-Fos, and c-Jun on the IL-10-induced inhibition of osteoclastogenesis. As expected, overexpression of NFATc1 abrogated the IL-10-induced inhibition of osteoclastogenesis. Interestingly, overexpression of either c-Fos or c-Jun partially rescued the reduction of RANKL-induced expression of NFATc1 and osteoclastogenesis by IL-10. These data suggest that IL-10 may down-regulate osteoclastogenesis mainly through inhibition of the expression of NFATc1, c-Fos and c-Jun. These findings provide new insight into the inhibitory action of IL-10 on RANKL-mediated osteoclastogenesis.

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