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-cellmediated 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 þ T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4 þ 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. Cancer Prev Res; 5(9); 1090-102. Ó2012 AACR.

Enterogenous bacterial glycolipids are required for the generation of natural killer T cells mediated liver injury

“…These data confirmed that glycolipids were less abundant in GF mice, thus providing a possibly explanation for the failure of ConA to activate hepatic NKT cells in GF mice. A previous study showed that the translocation of enterogenous LPS into the peripheral blood was significantly increased in ConA-treated compared to control mice20. In both GF and SPF mice after ConA administration, we detected edema and intestinal villus degradation for reasons that remain unknown, and the levels of several cytokines, including IFN-γ, IL-4, G-CSF, RANTES, MIP-1a and IL-6 were increased in the intestine after ConA treatment.…”

The microbiota regulates susceptibility to Fas-mediated acute hepatic injury

“…For example, liver damage resulting from administration of the hepatotropic T cell-activating lectin Concanavalin A (ConA) is reduced in mice deficient for the TLR signaling molecule MyD88 (6), suggesting that bacterial derived substances augment ConA mediated damage. Consistent with this observation, ConA induced inflammation and injury is ameliorated in mice treated with antibiotics, or deficient in TLR4 (7), implicating TLR4 ligands (e.g. LPS) in modulating disease.…”

Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein

“…The P-selectin expression was detected using Moflo-XDP system (Beckman-Coulter). The isolation of splenocytes and flow cytometry for detecting the splenic cells was performed as described previously 50 . Briefly, after the mouse was killed by CO 2 inhalation, the spleen was surgically removed, kept on ice in sterile RPMI1640 supplemented with 1% FBS and pressed through a cell strainer (70 mm Nylon).…”