title: Gut-derived lipopolysaccharide promotes T-cell-mediated hepatitis in mice through Toll-like receptor 4.
abstract: Robust clinical and epidemiologic data support the role of inflammation as a key player in hepatocellular carcinoma (HCC) development. Our previous data showed that gut-derived lipopolysaccharide (LPS) promote HCC development by activating Toll-like receptor 4 (TLR4) expressed on myeloid-derived cells. However, the effects of gut-derived LPS on other types of liver injury models are yet to be studied. The purpose of this study was to determine the importance of gut-derived LPS and TLR4 signaling in a T-cell-mediated hepatitis-Con A-induced hepatitis model, which mimic the viral hepatitis. Reduction of endotoxin using antibiotics regimen or genetic ablation of TLR4 in mice significantly alleviate Con A-induced liver injury by inhibiting the infiltration of T lymphocytes into the liver and the activation of CD4(+) T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4(+) T cells activation in vivo and in vitro. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored Con A-induced liver injury and inflammation, indicating the major cell target of LPS. In addition, TLR4 may positively regulate the target hepatocellular apoptosis via the perforin/granzyme B pathway. These data suggest that gut-derived LPS and TLR4 play important positive roles in Con A-induced hepatitis and modulation of the gut microbiotia may represent a new avenue for therapeutic intervention to treat acute hepatitis induced by hepatitis virus infection, thus to prevent hepatocellular carcinoma.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Le-Xing
authors.initials: LX
authors.lastname: Yu
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zou
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: He
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006505:Hepatitis / Q000276:immunology*; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4