담즙정체성 간섬유증에서 헬리코박터 파일로리균 감염의 병리효과

Helicobacter Pylori Exacerbates Cholestasis-induced Hepatic Fibrosis by Control of Regulatory T Cell and TLR4 Responses

Accumulating evidence implicates Helicobacter pylori (H. pylori) could be an exacerbating factors in liver diseases. However, local hepatic immune response induced by H. pylori infection is poorly understood. To clarify immunopathological effect of H. pylori infection on the progression of hepatic fibrosis, C57BL/6 mice were orally inoculated with H. pylori (1×108 CFU/100 μl) for 16 weeks and liver fibrosis was then induced by bile duct-ligation (BDL). H. pylori infection induced increased number of regulatory T cells (Tregs) in the liver, chronic hepatitis, and upregulation of profibrogenic cytokine (TGF-β and IL-6) levels in the liver. In addition, the expression of MCP-1, MIP-1α and RANTES, potent mediator of macrophage and T lymphocyte recruitment, were increased in H. pylori-infected liver. Consistently, we found that H. pylori+BDL-treated mice had enhanced hepatic fibrosis and fibrogenic immune responses compared to BDL-treated mice. Finally, H. pylori–induced profibrogenic responses were significantly suppressed in TLR4 knockout mice, indicating that H. pylori-induced liver fibrosis is dependent on TLR4 signaling. These results are in line with the conclusion that H. pylori-associated Treg and TLR4 responses are, at least in part, responsible for the development of liver fibrosis.