Regulation of Th17 Differentiation by Epidermal Fatty Acid-Binding Protein
Year: 2009
Type: article
Abstract: 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.
Source: The Journal of Immunology
Institutions: University of Louisville, University of Minnesota
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Fatty Acid Binding Proteins in Macrophage Function, G182854015, G2480908454, Fatty acid binding proteins in macrophage function, Lipid Binding Proteins in Obesity and Diabetes Syndromes, Fatty Acid Binding Proteins in Macrophage Function, Lipid Binding Proteins in Obesity and Diabetes Syndromes
OpenAlex ID: W1955140130