title: Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1.
abstract: Ethanol-induced liver injury is a complex process dependent upon the interaction of multiple cell types in the liver, as well as activation of the innate immune response. Increased expression of CYP2E1 in response to high concentrations of ethanol leads to greater production of cytotoxic ethanol metabolites, which in turn contribute to production of reactive oxygen species, oxidative stress, and ultimately, cell death. Necroptotic hepatocyte cell death in response to ethanol is mediated via a CYP2E1-dependent expression of receptor-interacting protein kinase 3 (RIP3), a key component of the necroptosome. In response to alarmins released during ethanol-induced necroptosis, the innate immune response is activated. Macrophage migration inhibitory factor (MIF), a pro-inflammatory multikine involved in many disease processes, is an essential component to this response to injury. MIF expression is increased during ethanol exposure via a CYP2E1-dependent pathway, likely contributing to an exacerbated innate immune response and chronic inflammation after chronic ethanol. This review will discuss the complex interactions between CYP2E1-dependent expression of RIP3 and MIF in the pathophysiology of chronic ethanol-induced liver injury.
authors.affiliation: Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States ; Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Barnes
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.affiliation: Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States ; Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH, United States ; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000818:Animals; D016923:Cell Death / Q000276:immunology; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*
chemical_list: D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1
keywords: Alcoholic liver disease; Cell death; Chemokines; Innate immunity; Necroptosis