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http://dx.doi.org/10.14348/molcells.2015.0218

Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells  

Lee, Young-Sun (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Yi, Hyon-Seung (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Suh, Yang-Gun (Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center)
Byun, Jin-Seok (Department of Oral Medicine, School of Dentistry, Kyungpook National University)
Eun, Hyuk Soo (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Kim, So Yeon (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Seo, Wonhyo (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Jeong, Jong-Min (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Choi, Won-Mook (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Kim, Myung-Ho (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Kim, Ji Hoon (Department of Internal Medicine, Korea University College of Medicine)
Park, Keun-Gyu (Department of Internal Medicine, Kyungpook National University School of Medicine)
Jeong, Won-Il (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
Publication Information
Molecules and Cells / v.38, no.11, 2015 , pp. 998-1006 More about this Journal
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 knockout ($Raldh1^{-/-}$), $CCL2^{-/-}$ 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-${\gamma}$ in T cells. Moreover, interferon-${\gamma}$ 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.
Keywords
4-methylpyrazole; concanavalin A; Hepatic stellate cells; interferon-gamma;
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