6533b7d8fe1ef96bd1269598

RESEARCH PRODUCT

Rôle du récepteur nucléaire d'activation et de prolifération des péroxysomes (PPAR-alpha) dans la modulation de l'inflammation et l'activation des cellules T

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We assessed, in this study, the effects of PPARα deficiency on the expression of mRNAencoding for insulin gene transcription factors in pancreatic β-cells along with thoseimplicated in inflammation in adipose tissues. On fasting, the adult PPARα-null mice werehypoglycemic. Serum insulin concentrations and its pancreatic mRNA transcripts weredownregulated in PPARα-null mice, suggesting that PPARα gene deletion contributes to lowinsulin gene transcription. The PPARα gene deletion downregulates the mRNA expression ofinsulin gene transcription factors, i.e., Pdx-1, Nkx6.1 and MafA. Besides, the pancreaticfunction was diminished by PPARα deficiency as PPARα-null mice expressed low pancreaticGlut2 and glucokinase mRNA. PPARα-null mice also expressed high adiponectin and leptinmRNA levels compared to wild type animals. Adipose tissues of PPARα-null mice exhibitedupregulation of CD14 and CD68 mRNA, generally expressed by macrophages. PPAR-a genedeletion downregulates the adipocyte mRNA of certain pro inflammatory agents, like MCP-1,TNF-a, IL-1b, IL-6, and RANTES, though pro-inflammatory TLR-2 and TLR-4 mRNAswere upregulated in the adipose tissues. Our results suggest that PPAR-a deficiency, in mice,is implicated in the modulation of insulin gene transcription and inflammatory status inadipose tissues.The another part of the study was conducted on CD4+ T-cells, isolated from wild type(WT) and PPARα-null mice, in order to assess the mechanismof action of docosahexaenoicacid (DHA), an n-3 fatty acid, in the modulation of two transcription factors, i.e., T-bet andGATA-3, implicated in T-cell differentiation towards, respectively, TH1 and TH2 phenotype.The T-cells from PPARα-null mice secreted higher IFN-γ and lower IL-4 concentrations thanWT T-cells. Furthermore, the deletion of PPAR-α gene in T-cells resulted in the upregulationof T-bet and downregulation of GATA-3 both at mRNA and protein levels. DHA exerted notonly an inhibitory effect on T-cell proliferation, but also diminished IFN-γ and stimulated IL-4 secretions in both cell types. DHA also downregulated T-bet and upregulated GATA-3 bothat transcription and protein levels. Though the T-cells from PPARα-null mice expressedhigher p38 phosphorylation than WT T-cells, DHA diminished the MAP kinasephosphorylation (p38 and ERK1/2) in both the cell types. The pharmacological inhibitors ofMAP kinases also downregulated T-bet and upregulated GATA-3 in T-cells. Altogether, theseresults demonstrate that DHA, via its action on MAP kinases, modulates the expression oftranscription factors. These results also explain the mechanism of action of this fatty acid onT-cell differentiation in disease and health