title: Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.
abstract: Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis.
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.|Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705, Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.|Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 305-764, Korea.
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.
authors.forename: Yang-Gun
authors.initials: YG
authors.lastname: Suh
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Byun
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Hyuk Soo
authors.initials: HS
authors.lastname: Eun
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Wonhyo
authors.initials: W
authors.lastname: Seo
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Jeong
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Won-Mook
authors.initials: WM
authors.lastname: Choi
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Myung-Ho
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705, Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 41566, Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity*; D000077604:Fomepizole; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D011720:Pyrazoles; D003208:Concanavalin A; D014801:Vitamin A; D014212:Tretinoin; D007371:Interferon-gamma; D000077604:Fomepizole; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase
keywords: 4-methylpyrazole; Hepatic stellate cells; concanavalin A; interferon-gamma