| Acute liver failure is a devastating liver disease associated with signi?cant mortality (40%-80%), characterized by the sudden onset in a patient of severe acute hepatitis. It can be caused by many kinds of reasons, such as virus infection, autoimmunity dysfunction, alcohol consumption, hepatotoxins intake and so on, however, the underlying pathophysiological mechanisms are not well understood. Development of new drugs depends primarily on the availability of suitable animal models.Concanavalin A has high affinity toward the hepatic sinus, leading to T-cell activation in the liver. ConA-induced hepatitis is a well-known experimental murine model that can mimic many kinds of human T cell-mediated hepatitis, with significantly elevated levels of transaminase as well as severe liver injury. Previous studies have identified that in Concanavalin A-mediated hepatitis model activated T cells and NKT cells release a series of cytokins that play great roles in the liver injury. Different cytokins can be categorized as Th1 and Th2 associated cytokines by their biological function. Studies have illustrated that Th1 associated cytokines such as IL-12 and IFN-γare dominant factors inducing the development of Th1 cells. Conversely, IL-4 production directs the development of a Th2 response. Th1 cells mediate delayed type hypersensitivity responses and provide protection against intracellular pathogens and viruses, Th2 cells provide help to B cells and eradicate helminthes and other extra-cellular parasites. Th1/Th2 differentiation of T cells is largely dependent on the balance of GATA-3 and T-bet. The balance of Th1 and Th2 cells exerts an crucial role in keeping normal immunoregulation, however, in pathologic conditions such as allergic and autoimmune diseases, polarized Th1 and Th2 responses are found and believed to be critical to the outcome of these conditions.Emerging evidence suggests a strong interaction between the gut microbiota and human disease. Receiving～70% of its blood supply from the intestine through the portal circulation, the liver is the ?rst line of defense against gut-derived antigens. In order to cope with these latent systemic pathogens the liver contains a large number of resident immune cells such as macrophages, natural killer cells, dendritic cells, T and B lymphocytes. The resident macrophages of the liver, Kupffer cells, are able to take up ef?ciently endotoxin and phagocytose bacteria carried through portal vein blood, hepatocytes are also a major cell type involved in LPS uptake. Despite the constant exposure to low levels of gut-derived bacteria and bacterial products, there are no obvious inflammation in the healthy liver. However, when normal liver physiology is disrupted and inflammatory cells are activated, gut-derived factors likely augment or exacerbate certain liver diseases leading to enhanced tissue damage and propagation of inflammation via activation of TLR-signaling pathways.The role of gut-derived endotoxin in liver disease has excited much interest in investigators for a long time, and the critical role of gut-derived endotoxin as a cofactor in acute and chronic liver disease, both experimental and clinical, was already established more than 30-40 years ago. Our previous study also demonstrated that the endotoxin/TLR4 regulates the survival and proliferation of hepatocytes and their preneoplastic derivatives during chemically induced hepatocarcinogenesis.Toll like receptors (TLRs) recognize pathogen-associated molecular patterns and activate signaling pathways that lead to the induction of innate immune and inflammatory genes. In addition, there is accumulating evidence that TLRs contribute signi?cantly to activation of adaptive immune responses such as dendritic cell maturation and T- and B-cell responses,specially, the TH1-dependent immune responses. TLR4 is an important member of TLRs, which could sense endotoxin and activate transcription factors that initiate innate immunity. Previous study displayed that TLR4 was also expressed on T lymphocyte, playing a vital role in adaptive immunity. Recent studies have demonstrated the contribution of TLR4 signaling to the trapping of CD8+ T cells within the murine liver. Moreover, other very recent studies indicate that direct interactions of gut-derived antigens signaling through Toll like receptor 4 on CD4+ T cells contributes to their regulatory development and function. We hypothesize that gut-derived LPS and TLR4 may have some roles in ConA-induced hepatitis, which predominantly mediated by T lymphocytes in liver.In the current study, we report that there is a sustained LPS accumulation in ConA-induced hepatitis model. Deletion of gut microflora using antibiotics and TLR4 deficiency can decrease the accumulation of endotoxin efficiently and markedly suppress the liver injury induced by ConA. This attenuated hepatitis seen in both antibiotics-treatment mice and TLR4 knockout (TLR4-/-) mice primarily results from the reduced infiltration of T lymphocytes and suppressed activation of CD4+ T cells as well as decreased levels of Th1 cytokine production in response to ConA stimulation. Furthermore, deletion of gut microflora and TLR4 deficiency lighten liver injury induced by ConA through promoting the activation of Erk1/2, in addition, perforin/granzyme B mechanism may involve in the protection of TLR4 ablation. These results suggest that preventing plasma endotoxin accumulation could have a beneficial impact on liver function for patients with T cell-mediated hepatisis.
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