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* Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40292; and
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455
Epidermal fatty acid-binding protein, E-FABP, a lipid chaperone, has been shown to regulate the inflammatory function of macrophages and dendritic cells. Herein, we demonstrate that T cell expression of E-FABP promotes Th17 differentiation, while counterregulating development of FoxP3+ regulatory T cells (Tregs). In response to immunization with myelin oligodendrocyte glycoprotein peptide (MOG35–55), E-FABP-deficient mice generated reduced levels of Th17 cells and elevated levels of Tregs, as compared with wild-type mice. Likewise, naive CD4+ T cells isolated from E-FABP-deficient mice showed reduced expression of IL-17 and enhanced expression of FoxP3, in vitro, when subjected to Th17 or Treg polarizing conditions, respectively. It has been demonstrated previously that IL-21, induced by IL-6, stimulates the expression of the nuclear receptors retinoic acid-related orphan receptor (ROR)
t and ROR
, which in turn induce expression of IL-17. We found that the impaired Th17 differentiation by E-FABP-deficient CD4+ T cells was associated with lower levels of IL-21 expression in response to IL-6, as well as reduced expression of RORt and ROR. However, E-FABP-deficient CD4+ T cells expressed significantly higher levels of the nuclear receptor peroxisome proliferator-activating receptor (PPAR) than did wild-type CD4+ T cells, and treatment with the PPAR antagonist GW9662 restored expression of IL-21, RORt, ROR, and IL-17 by E-FABP-deficient T cells to wild-type levels. The negative influence of E-FABP deficiency on IL-17 expression was attributed to PPAR-mediated suppression of IL-6-induced STAT3 activity. Thus, taken together, our data indicate that expression of E-FABP by CD4+ T cells contributes to the control of IL-6 stimulation of the IL-21/ROR/IL-17 pathway and to the Th17/Treg counterbalance.
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1 This work was supported by National Institutes of Health Grants AI048850 (to J.S.) and DK053189 (to D.A.B.), National Multiple Sclerosis Society Grant RG 3374 (to J.S.), by an American Heart Association Predoctoral Fellowship (to J.M.R.), and, in part, by the Commonwealth of Kentucky Research Challenge Trust Fund (to J.S. and R.D.S.).
2 Address correspondence and reprint requests to Dr. Jill Suttles, Department of Microbiology and Immunology, School of Medicine, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40292. E-mail address: jill.suttles{at}louisville.edu
3 Abbreviations used in this paper: FABP, fatty acid-binding protein; E-FABP, epidermal FABP; A-FABP, adipose FABP; DC, dendritic cell; PPAR, peroxisome proliferator-activating receptor; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; Treg, regulatory T cell; ROR, retinoic acid-related orphan receptor; RA, retinoic acid; ATRA, all-trans retinoic acid; 9-cis-RA, 9-cis retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; WT, wild type; 13-HODE, 13-hydroxyoctadecadienoic acid; DAPI, 4',6-diamidino-2-phenylindole.
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