TRIIODOTHYRONINE MODULATES INTERLEUKIN-6 SYNTHESIS IN OSTEOBLASTS - INHIBITIONS IN PROTEIN-KINASE-A AND PROTEIN-KINASE-C PATHWAYS

In osteoblast-like MC3T3-E1 cells, we recently reported that PGE(1) an d PGF(2 alpha) induce interleukin (IL)-6 synthesis via activation of p rotein kinase A and protein kinase C, respectively. Moreover, in the c ase of IL-1-induced IL-6 synthesis in these cells, we showed that prot ein kinase C activation by IL-1 limits the IL-6 synthesis. In the pres ent study, we investigated the effect of T-3 on IL-6 synthesis induced by these agonists in MC3T3-E1 cells. T-3, which by itself had little effect on IL-6 synthesis, significantly reduced the IL-6 synthesis ind uced by PGE(1) in a dose-dependent manner in the range between 10 pM a nd 10 nM. T-3 also reduced PGE(1)-induced activation of protein kinase A. T-3 inhibited the IL-6 synthesis induced by cholera toxin, an acti vator of G(S), or forskolin, which directly activates adenylate cyclas e. However, T-3 did not affect (Bu)(2)cAMP-induced IL-6 synthesis. In addition, T-3 reduced PGF(2 alpha)-induced IL-6 synthesis dose depende ntly in the range between 10 pM and 10 nM. T-3 also inhibited IL-6 syn thesis induced by 12-O-tetradecanoylphorbol-13-acetate, an activator o f protein kinase C. On the other hand, T-3 markedly enhanced IL-1-indu ced IL-6 synthesis. This enhancement by T-3 was potentiated in protein kinase C down-regulated cells. T-3 hardly affected the protein kinase C activation induced by PGF(2 alpha) or IL-1. These results strongly suggest that T-3 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.