Pharmacological application of caffeine inhibits TGF-β-stimulated connective tissue growth factor expression in hepatocytes via PPARγ and SMAD2/3-dependent pathways

Background/Aims: Epidemiological studies suggest that coffee drinking is inversely correlated with the risk of development of liver fibrosis but the molecular basis is unknown. Methods: We investigated the pharmacological mechanisms involved in caffeine-dependent regulation of CTGF expression, an important modulator protein of fibrogenic TGF-beta, in rat hepatocytes using Western-blot, co-immunoprecipitations, reporter-gene-assays and ELISAs. Results: It is demonstrated that caffeine, similar to 8-Br-cAMP, suppresses CTGF expression, decreases SMAD2 protein levels and inhibits SMAD1/3-phosphorylation. The SMAD2 level can be restored by a proteasome inhibitor. Additionally, caffeine leads to an up-regulation of PPAR gamma expression, that enhances the inhibitory effect of the natural PPAR gamma agonist 15-PGJ(2) on CTGF expression by inducing a dissociation of the SMAD2/3-CBP/p300-transcriptional complex. Conclusions: We show that caffeine strongly down-modulates TGF-beta-induced CTGF expression in hepatocytes by stimulation of degradation of the TGF-beta effector SMAD 2, inhibition of SMAD3 phosphorylation and up-regulation of the PPAR gamma-receptor. Long-term caffeinization might be an option for anti-fibrotic trials in chronic liver diseases. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.