Gut-derived lipopolysaccharide promotes T-cell-mediated hepatitis in mice through Toll-like receptor 4 - PubMed (original) (raw)
. 2012 Sep;5(9):1090-102.
doi: 10.1158/1940-6207.CAPR-11-0364. Epub 2012 May 22.
Le-Xing Yu, He-Xin Yan, Wen Yang, Liang Tang, Hui-Lu Zhang, Qiong Liu, Shan-Shan Zou, Ya-Qin He, Chao Wang, Meng-Chao Wu, Hong-Yang Wang
Affiliations
- PMID: 22617167
- DOI: 10.1158/1940-6207.CAPR-11-0364
Gut-derived lipopolysaccharide promotes T-cell-mediated hepatitis in mice through Toll-like receptor 4
Yan Lin et al. Cancer Prev Res (Phila). 2012 Sep.
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.
Comment in
- The great escape: microbiotal LPS takes a toll on the liver.
Weiss DS. Weiss DS. Cancer Prev Res (Phila). 2012 Sep;5(9):1078-80. doi: 10.1158/1940-6207.CAPR-12-0248. Cancer Prev Res (Phila). 2012. PMID: 22952210 Free PMC article.
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