After in vitro stimulation, the percentage of IL-17A-producing γδ T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified γδ T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL-17A were

reduced after inhibition of macrophages and could not be induced in Toll-like receptor TLR4−/− mice after acetaminophen challenge. Meanwhile, serum high-mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased Protein Tyrosine Kinase inhibitor after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4+/+ but not by TLR4−/− macrophages. Conclusion: The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing γδ T cells, which mediates neutrophil infiltration and damage-induced liver inflammation. (HEPATOLOGY 2013) Acetaminophen is usually used as an over- the-counter analgesic and antipyretic drug. However, acetaminophen overdose has become a frequent cause of intentional or accidental death in many countries.1, 2 Acetaminophen is metabolized by hepatic CYP2E1 into the toxic intermediate N-acetyl-p-benzoquinone-imine, which is then detoxified by hepatic glutathione. However,

excessive N-acetyl-p-benzoquinone-imine consumes hepatic glutathione Selleck Veliparib and covalently binds cellular proteins, resulting in hepatocyte necrosis.3, 4 Because the innate immune response following hepatocyte necrosis has been noted to cause a second wave of liver destruction,5, 6 the overall progression is now described by a “two-hit” model.7 Natural killer (NK) and natural killer T (NKT) cells have been reported to play a pathogenic role in the progression of acetaminophen-induced liver injury by up-regulating Fas ligand and secreting interferon

(IFN)-γ. Depletion of NK/NKT cells significantly ameliorates liver injury.8 However, Masson et al.9 revealed that the role of NK and NKT cells in these studies was dependent on dimethyl sulfoxide (DMSO), the solvent used to dissolve acetaminophen in the experiments. That group found Glutamate dehydrogenase that low levels of DMSO could recruit NKT cells to the liver and activate NK and NKT cells. In the absence of DMSO, NK and NKT cells did not produce IFN-γ after acetaminophen challenge, and depletion of these cells did not protect mice from acetaminophen-induced liver injury. However, increasing evidence has demonstrated that the innate immune response does participate in the pathogenesis of acetaminophen-induced injury, even in the absence of DMSO. Thus, understanding the critical immune cells and cytokines that mediate acetaminophen-induced liver injury is important. Imaeda et al.