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Inhibition of Interleukin-4 Production in CD4⁺ T Cells by Peroxisome Proliferator-Activated Receptor- (PPAR-) Ligands: Involvement of Physical Association between PPAR- and the Nuclear Factor of Activated T Cells Transcription Factor

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju, Republic of Korea (S.W.C., T.S.K.); and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts (B.Y.K.)

Peroxisome proliferator-activated receptor- (PPAR-) has been implicated in the regulation of multiple inflammatory processes. However, little is known of PPAR- in the regulation of interleukin (IL)-4 expression in T cells. In this study, the effects of PPAR- ligands on production of IL-4, a pro-inflammatory cytokine associated with the pathophysiology of allergic diseases, were investigated. 15-Deoxy-^12,14 prostaglandin J₂ (15d-PGJ₂) and ciglitazone, two representative PPAR- 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- ligands. In cotransfected EL-4 T cells, PPAR- also inhibited the activation of the IL-4 promoter at multiple NF-AT sites in a ligand-dependent manner. NF-ATc1 bound PPAR- both in vivo and in vitro, and the interaction interfaces involved the Rel similarity domain of NF-ATc1. In cotransfections of HeLa cells, PPAR- inhibited the NF-ATc1 transactivation in a ligand-dependent manner. Coexpression of p300 or AP-1 relieved the PPAR- ligand-mediated inhibition of the NF-AT transactivation. From these results, we propose that PPAR- 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-.

Address correspondence to: Dr. Tae Sung Kim, College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju 500-757, Republic of Korea. E-mail: taekim{at}chonnam.ac.kr

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