Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors

Biol Pharm Bull. 2017;40(5):658-664. doi: 10.1248/bpb.b16-00947.

Abstract

During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca2+ chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.

Keywords: Akt1; adenosine receptor; cAMP; caffeine; hepatic stellate cell; transformation.

MeSH terms

  • Animals
  • Caffeine / pharmacology*
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Cyclic AMP / metabolism*
  • Dose-Response Relationship, Drug
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Hepatic Stellate Cells / drug effects*
  • Liver Cirrhosis / drug therapy
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphorylation
  • Quinazolines / pharmacology
  • Receptors, Purinergic P1 / drug effects*
  • Triazoles / pharmacology

Substances

  • Chelating Agents
  • Phosphodiesterase Inhibitors
  • Quinazolines
  • Receptors, Purinergic P1
  • Triazoles
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Caffeine
  • Egtazic Acid
  • Cyclic AMP
  • 9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine