[No authors listed]
Heat shock protein 90 (HSP90), expressed abundantly in a variety of cell types, is a molecular chaperone, and has a central role in protein homeostasis under stress conditions. In our previous study, it was shown that thrombin stimulates interleukinâ6 (ILâ6) synthesis via p44/p42 mitogenâactivated protein kinase (MAPK) and p38 MAPK in osteoblastâlike MC3T3âE1 cells, and that Rhoâkinase acts as a positive regulator at a point upstream of p38 MAPK, but not p44/p42 MAPK. The present study investigated whether or not HSP90 is involved in the thrombinâstimulated synthesis of ILâ6 and examined the mechanism by which HSP90 is involved in MC3T3âE1 cells. Cultured cells were stimulated by treatment with thrombin. ILâ6 concentrations in MC3T3âE1 cells were determined using an ELISA assay, and levels of phosphorylated p38 MAPK, p44/p42 MAPK and myosin phosphatase targeting subunit, a substrate of Rhoâkinase; were analyzed by western blotting. The 17âallylaminoâ17demethoxyâgeldanamycin (17âAAG) and 17âdimethylaminoâethylaminoâ17âdemethoxyâgeldanamycin (17âDMAG) HSP90 inhibitors significantly enhanced the thrombinâstimulated release of ILâ6. Geldanamycin, another inhibitor of HSP90, also upregulated the release and mRNA expression of ILâ6. 17âAAG and geldanamycin markedly potentiated the thrombinâinduced phosphorylation of p38 MAPK without affecting the phosphorylation of p44/p42 MAPK or myosin phosphatase targeting subunit, a substrate of Rhoâkinase. Additionally, the enhancement by 17âAAG of the thrombinâstimulated release of ILâ6 was significantly reduced by SB203580, an inhibitor of p38 MAPK. These results suggested that the thrombinâstimulated synthesis of ILâ6 was limited by HSP90 in osteoblasts, and that the effects of HSP90 were exerted at the point between Rhoâkinase and p38 MAPK.
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