Poster Presenter

Pharmacological Application of Caffeine Inhibits TGF-β-Dependent Connective Tissue Growth Factor (CTGF/CCN2) Expression in Hepatocytes in vitro and in the D-Galactosamine Damaged Liver in vivo
Gressner OA, Lahme B, Siluschek M, Gressner AM
Germany

Introduction: Several epidemiological studies suggest that coffee drinking is an environmental risk modulator of hepatic fibrogenesis.
Aim and Methods: We investigated the effects of caffeine on TGF CTGF-expression in rat hepatocytes as well as during in vivo liver damage by western-blot, co-immunoprecipitations, luminometric-and reporter-gene-assays, ELISA and immunohistochemistry.

Results: We demonstrate that caffeine increases cAMP-levels in hepatocytes and that it reduces total Smad2 protein-concentrations and Smad1/3-phosphorylation in hepatocytes which can be reversed by inhibition of the proteasome/ubiquitination system (SMURF2). In vivo liver damage in the rat by D-GalN lead to increased hepatic CTGF expression which could be attenuated by simultaneous i.p. administration of caffeine. Furthermore, application of caffeine resulted in a striking increase of hepatic cAMP levels, and markedly reduced serum CTGF concentrations.

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-β effector Smads 2 and 3. These data are confirmed by the findings that caffeine suppresses hepatic CTGF expression in livers exposed to D-GalN such as the spill-over of CTGF into the circulation. Considering earlier reports that silencing of CTGF by siRNA in vivo almost entirely inhibits fibrotic remodeling of livers in mice previously subjected to hepatotoxic agents, our data could propose long-term caffeinization as a potential therapeutic option in the management of chronic liver disease.