Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

Our earlier report has shown that Helicobacter pylori promoted hepatic fibrosis in a murine model. Herein, in order to elucidate the mechanism by which H. pylori accelerate liver fibrosis, the authors investigated the changes in expression levels of mitogen-activated protein kinases (MAPKs), p53-related proteins, antioxidants, and proinflammatory cytokines in liver samples. H. pylori infection enhanced CCl4-induced MAP kinase activation and p53 signaling pathway as well as Bax-and proliferating-cell nuclear antigen expressions, whereas H. pylori alone induced neither of these expressions nor hepatic fibrosis. Moreover, mRNA expressions of inflammatory cytokines, glutathione peroxidase expression, and the proliferative index were strongly augmented in livers of the H. pylori with CCl4 treatment group compared with those of the CCl4-alone treatment group, whereas there was no difference in apoptotic index between the two groups. Interestingly, H. pylori treatment increased the number of a-fetoprotein-expressing hepatocytes independently of CCl4 intoxication. In vitro analyses, using an immortalized rat hepatic stellate cell (HSC) line, revealed that H. pylori lysates increased the proliferation of HSCs, which was boosted by the addition of transforming growth factor-beta1 (TGF-beta 1). Furthermore, the treatment of H. pylori lysates promoted the translocation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappa B) into the nucleus based on an increase in the degradation of NF-kB inhibitor alpha, in the presence of TGF-beta 1, as did H2O2 treatment. In conclusion, H. pylori infection along with an elevated TGF-beta 1 may accelerate hepatic fibrosis through increased TGF-beta 1-induced pro-inflammatory signaling pathways in HSCs. Moreover, H. pylori infection might increase the risk of TGF-beta 1-mediated tumorigenesis by disturbing the balance between apoptosis and proliferation of hepatocytes. Laboratory Investigation (2010) 90, 1507-1516; doi: 10.1038/labinvest.2010.109; published online 7 June 2010