Pharmacological application of caffeine inhibits TGF-β-stimulated connective tissue growth factor (CTGF/CCN2) expression in hepatocytes via PPARγ and Smad2/3-dependent pathways

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Abstract
Introduction: Several epidemiological studies suggest that coffee drinking is an environmental risk modulator of hepatic fibrogenesis. Methods: We investigated the molecular events involved in caffeine-induced inhibition of TGF-β dependent and independent CTGF-expression in primary rat hepatocytes by western-blot, co-immunoprecipitations, luminometric- and reporter-gene-assays and ELISA. Results: We demonstrate that Caffeine increases cAMP-levels in hepatocytes. Administration of 8-Br-cAMP and caffeine suppresses CTGF-expression, Smad2 protein-levels and Smad1/3-phosphorylation in hepatocytes which can be reversed by inhibition of the proteasome/ubiquitination system and which is accompanied by increased SMURF2-consumption. Furthermore, caffeine leads to an upregulation of PPARγ-expression, the PPARγ agonist 15-PGJ2 significantly suppresses CTGF-expression in hepatocytes by dissociation of the Smad2/3-CBP/p300-transcriptional complex. Conclusion: We show that the food-compound caffeine down-modulates TGF-β induced CTGF-expression in hepatocytes via a stimulation of degradation of the TGF- effector Smads 2 and 3 and via an upregulation of the PPARγ-receptor. Long-term caffeinization might thus be an option in the antifibrotic treatment of chronic liver diseases.

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