title: CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+ T cells aid progression of environment-linked nonalcoholic steatohepatitis.
abstract: Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8+CD57+ cytotoxic T cells but not CD4+CD57+ cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8+CD57+ T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH.
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Ratanesh Kumar
authors.initials: RK
authors.lastname: Seth
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Suvarthi
authors.initials: S
authors.lastname: Das
authors.affiliation: Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Chanda
authors.affiliation: Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Kadiiska
authors.affiliation: Division of Gastroenterology, Duke University, Durham, NC 27707, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Michelotti
authors.affiliation: Dept. of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Manautou
authors.affiliation: Division of Gastroenterology, Duke University, Durham, NC 27707, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA. Electronic address: schatt@mailbox.sc.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D018959:CD57 Antigens / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency*; D016207:Cytokines / Q000096:biosynthesis; D004781:Environmental Exposure / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D020738:Leptin / Q000172:deficiency*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D022882:Trihalomethanes / Q000633:toxicity
chemical_list: D018959:CD57 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D020738:Leptin; D022882:Trihalomethanes; C025191:bromodichloromethane; D019392:Cytochrome P-450 CYP2E1
keywords: Apoptosis; Bromodichloromethane; CD3; IL-2; Leptin; Lipid peroxidation