Blockade of retinol metabolism protects T cell-induced hepatitis by increasing migration of regulatory T cells

Young-Sun Lee, Hyon Seung Yi, Yang Gun Suh, Jin Seok Byun, Hyuk Soo Eun, So Yeon Kim, Wonhyo Seo, Jong Min Jeong, Won Mook Choi, Myung Ho Kim, Ji Hoon Kim, Keun Gyu Park, Won Il Jeong

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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. 1 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 Amediated hepatitis by decreasing interferon-γin 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 Ainduced 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.

Original languageEnglish
Pages (from-to)998-1006
Number of pages9
JournalMolecules and Cells
Volume38
Issue number11
DOIs
Publication statusPublished - 2015 Jan 1

Fingerprint

Regulatory T-Lymphocytes
Vitamin A
Hepatitis
Hepatic Stellate Cells
T-Lymphocytes
Interleukin-6
Adoptive Transfer
Alcohol Dehydrogenase
Concanavalin A
Interferons
Retinaldehyde
Tretinoin
Oxidoreductases
Therapeutics
Liver
Wounds and Injuries
Genes

Keywords

  • 4-methylpyrazole
  • Concanavalin A
  • Hepatic stellate cells
  • Interferon-gamma

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Blockade of retinol metabolism protects T cell-induced hepatitis by increasing migration of regulatory T cells. / Lee, Young-Sun; Yi, Hyon Seung; Suh, Yang Gun; Byun, Jin Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong Min; Choi, Won Mook; Kim, Myung Ho; Kim, Ji Hoon; Park, Keun Gyu; Jeong, Won Il.

In: Molecules and Cells, Vol. 38, No. 11, 01.01.2015, p. 998-1006.

Research output: Contribution to journalArticle

Lee, Y-S, Yi, HS, Suh, YG, Byun, JS, Eun, HS, Kim, SY, Seo, W, Jeong, JM, Choi, WM, Kim, MH, Kim, JH, Park, KG & Jeong, WI 2015, 'Blockade of retinol metabolism protects T cell-induced hepatitis by increasing migration of regulatory T cells', Molecules and Cells, vol. 38, no. 11, pp. 998-1006. https://doi.org/10.14348/molcells.2015.0218
Lee, Young-Sun ; Yi, Hyon Seung ; Suh, Yang Gun ; Byun, Jin Seok ; Eun, Hyuk Soo ; Kim, So Yeon ; Seo, Wonhyo ; Jeong, Jong Min ; Choi, Won Mook ; Kim, Myung Ho ; Kim, Ji Hoon ; Park, Keun Gyu ; Jeong, Won Il. / Blockade of retinol metabolism protects T cell-induced hepatitis by increasing migration of regulatory T cells. In: Molecules and Cells. 2015 ; Vol. 38, No. 11. pp. 998-1006.
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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. 1 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 Amediated hepatitis by decreasing interferon-γin 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 Ainduced 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.",
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