Regulation of Th17 differentiation by epidermal fatty acid-binding protein.
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 (MOG(35-55)), 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)gammat and RORalpha, 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 RORgammat and RORalpha. However, E-FABP-deficient CD4(+) T cells expressed significantly higher levels of the nuclear receptor peroxisome proliferator-activating receptor (PPAR)gamma than did wild-type CD4(+) T cells, and treatment with the PPARgamma antagonist GW9662 restored expression of IL-21, RORgammat, RORalpha, 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 PPARgamma-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.
Li
Bing
B
Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Reynolds
Joseph M
JM
Stout
Robert D
RD
Bernlohr
David A
DA
Suttles
Jill
J
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology
C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D009363:Neoplasm Proteins; D047495:PPAR gamma; D014212:Tretinoin