title: Macrophage migration inhibitory factor triggers chemotaxis of CD74+CXCR2+ NKT cells in chemically induced IFN-γ-mediated skin inflammation.
abstract: IFN-γ mediates chemically induced skin inflammation; however, the mechanism by which IFN-γ-producing cells are recruited to the sites of inflammation remains undefined. Secretion of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, from damaged cells may promote immune cell recruitment. We hypothesized that MIF triggers an initial step in the chemotaxis of IFN-γ-producing cells in chemically induced skin inflammation. Using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears, MIF expression was examined, and its role in this process was investigated pharmacologically. The cell populations targeted by MIF, their receptor expression patterns, and the effects of MIF on cell migration were examined. TPA directly caused cytotoxicity accompanied by MIF release in mouse ear epidermal keratinocytes, as well as in human keratinocytic HaCaT cells. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Inhibition of MIF greatly diminished the dermal infiltration of IFN-γ(+) NKT cells, whereas the addition of exogenous TPA and MIF to NKT cells promoted their IFN-γ production and migration, respectively. MIF specifically triggered the chemotaxis of NKT cells via CD74 and CXCR2, and the resulting depletion of NKT cells abolished TPA-induced skin inflammation. In TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74(+)CXCR2(+) NKT cells for IFN-γ production.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Center of Translational Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Tsung-Ting
authors.initials: TT
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Hong
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Translational Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan cflin2014@tmu.edu.tw.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000208:Acute Disease; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D002908:Chronic Disease; D004195:Disease Models, Animal; D003875:Drug Eruptions / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004817:Epidermis / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D002273:Carcinogens; D000949:Histocompatibility Antigens Class II; C573415:IFNG protein, human; D008263:Macrophage Migration-Inhibitory Factors; D023063:Receptors, Interleukin-8B; C045084:invariant chain; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse; D013755:Tetradecanoylphorbol Acetate