Triiodothyronine modulates interleukin-6 synthesis in osteoblasts: inhibitions in protein kinase A and C pathways

In osteoblast-like MC3T3-E1 cells, we recently reported that PGE1 and PGF2alpha induce interleukin (IL)-6 synthesis via activation of protein kinase A and protein kinase C, respectively. Moreover, in the case of IL-1-induced IL-6 synthesis in these cells, we showed that protein kinase C activation by IL-1 limits the IL-6 synthesis. In the present study, we investigated the effect of T3 on IL-6 synthesis induced by these agonists in MC3T3-E1 cells. T3, which by itself had little effect on IL-6 synthesis, significantly reduced the IL-6 synthesis induced by PGE1 in a dose-dependent manner in the range between 10 pM and 10 nM. T3 also reduced PGE1-induced activation of protein kinase A. T3 inhibited the IL-6 synthesis induced by cholera toxin, an activator of Gs, or forskolin, which directly activates adenylate cyclase. However, T3 did not affect (Bu)2cAMP-induced IL-6 synthesis. In addition, T3 reduced PGF2alpha-induced IL-6 synthesis dose dependently in the range between 10 pM and 10 nM. T3 also inhibited IL-6 synthesis induced by 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C. On the other hand, T3 markedly enhanced IL-1-induced IL-6 synthesis. This enhancement by T3 was potentiated in protein kinase C down-regulated cells. T3 hardly affected the protein kinase C activation induced by PGF2alpha or IL-1. These results strongly suggest that T3 modulates IL-6 synthesis at two points in osteoblasts as follows; one is exerted at the point between adenylate cyclase and protein kinase A, and the other is at a point downstream from protein kinase C activation.