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  • Title: Inhibition of interleukin-4 production in CD4+ T cells by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: involvement of physical association between PPAR-gamma and the nuclear factor of activated T cells transcription factor.
    Author: Chung SW, Kang BY, Kim TS.
    Journal: Mol Pharmacol; 2003 Nov; 64(5):1169-79. PubMed ID: 14573767.
    Abstract:
    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been implicated in the regulation of multiple inflammatory processes. However, little is known of PPAR-gamma in the regulation of interleukin (IL)-4 expression in T cells. In this study, the effects of PPAR-gamma ligands on production of IL-4, a pro-inflammatory cytokine associated with the pathophysiology of allergic diseases, were investigated. 15-Deoxy-Delta12,14 prostaglandin J2 (15d-PGJ2) and ciglitazone, two representative PPAR-gamma ligands, significantly inhibited IL-4 production in both antigen-stimulated primary CD4+ T cells and the phorbol 12-myristate 13-acetate (PMA)/ionomycin-activated EL-4 T cell line. 15d-PGJ2 and ciglitazone inhibited the activation of IL-4 gene promoter in EL-4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the repressive effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor of activated T cells (NF-AT). The activation of T cells by PMA/ionomycin resulted in a marked enhancement of the binding activities to the NF-AT site that was significantly inhibited by the addition of PPAR-gamma ligands. In cotransfected EL-4 T cells, PPAR-gamma also inhibited the activation of the IL-4 promoter at multiple NF-AT sites in a ligand-dependent manner. NF-ATc1 bound PPAR-gamma both in vivo and in vitro, and the interaction interfaces involved the Rel similarity domain of NF-ATc1. In cotransfections of HeLa cells, PPAR-gamma inhibited the NF-ATc1 transactivation in a ligand-dependent manner. Coexpression of p300 or AP-1 relieved the PPAR-gamma ligand-mediated inhibition of the NF-AT transactivation. From these results, we propose that PPAR-gamma ligand-mediated suppression of IL-4 production in CD4+ T cells may involve both inhibition of the NFAT-DNA interactions and competitive recruitment of transcription integrators between NF-AT and PPAR-gamma.
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