Glucocorticoids activate TGF-beta induced PAI-1 and CTGF expression in rat hepatocytes.

BACKGROUND: In addition to the activation of hepatic stellate cells TGF-beta govern apoptosis and growth control of hepatocytes in liver injury. In non-parenchymal cells, TGF-beta induces plasminogen activator inhibitor 1 (PAI-1) and connective tissue growth factor (CTGF) expression, which are involved in extra cellular matrix formation. Both genes were also regulated by glucocorticoids, which in certain cases showed antagonistic effects to the TGF-beta-Smad 3 pathway. The purpose of our work was to investigate the influence of TGF-beta and dexamethasone on PAI-1 and CTGF expression and secretion in primary hepatocytes. RESULTS: By examining PAI-1 and CTGF mRNA and protein expression in cell lysates and cell-conditioned media under the influence of TGF-beta and dexamethasone, we analysed signalling pathways controlling their expression. TGF-beta and dexamethasone significantly co-induce PAI-1 and CTGF protein expression. On the other hand, we showed that TGF-beta diminished a glucocorticoid receptor dependent luciferase reporter signal in Hep-G2. Inhibition of Erk downstream activation decreased TGF-beta induced CTGF and PAI-1 expression to a basal level. PAI-1 was directly secreted by hepatocytes, whereas secretion of CTGF was retarded. CONCLUSION: The data provide evidence that beside the TGF-beta-Smad 3 pathway CTGF and PAI-1 expression is additionally dependent on Erk activity in hepatocytes giving new insights into regulation of the profibrogenic proteins.