title: Retinoic acid alleviates Con A-induced hepatitis and differentially regulates effector production in NKT cells.
abstract: Retinoic acid (RA) is a diverse regulator of immune responses. Although RA promotes natural killer T (NKT) cell activation in vitro by increasing CD1d expression on antigen-presenting cells (APCs), the direct effects of RA on NKT-cell responses in vivo are not known. In the present study, we demonstrated the effect of RA on the severity of Con A-induced hepatitis and molecular changes of NKT cells. First, we demonstrated that Con A-induced liver damage was ameliorated by RA. In correlation with cytokine levels in serum, RA regulated the production of IFN-γ and IL-4 but not TNF-α by NKT cells without influencing the NKT-cell activation status. However, RA did not alleviate α-GalCer-induced liver injury, even though it reduced IFN-γ and IL-4 but not TNF-α levels in serum. This regulation was also detected when liver mononuclear cells (MNCs) or NKT hybridoma cells were treated with RA in vitro. The regulatory effect of RA on NKT cells was mediated by RAR-α, and RA reduced the phosphorylation of MAPK. These results suggest that RA differentially modulates the production of effector cytokines by NKT cells in hepatitis, and the suppressive effect of RA on hepatitis varies with the pathogenic mechanism of liver injury.
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Kyoo-A
authors.initials: KA
authors.lastname: Lee
authors.forename: You Chan
authors.initials: YC
authors.lastname: Song
authors.forename: Ga-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Gyeyoung
authors.initials: G
authors.lastname: Choi
authors.forename: Yoon-Sook
authors.initials: YS
authors.lastname: Lee
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Lee
authors.forename: Chang-Yuil
authors.initials: CY
authors.lastname: Kang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003208:Concanavalin A / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000276:immunology; D006505:Hepatitis / Q000188:drug therapy* / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000276:immunology; D000072482:Retinoic Acid Receptor alpha; D013047:Specific Pathogen-Free Organisms; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D005699:Galactosylceramides; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D003208:Concanavalin A; D015847:Interleukin-4; D014212:Tretinoin; D012313:RNA; D007371:Interferon-gamma