@article {Chung1169, author = {Su Wol Chung and Bok Yun Kang and Tae Sung Kim}, title = {Inhibition of Interleukin-4 Production in CD4+ T Cells by Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Ligands: Involvement of Physical Association between PPAR-γ and the Nuclear Factor of Activated T Cells Transcription Factor}, volume = {64}, number = {5}, pages = {1169--1179}, year = {2003}, doi = {10.1124/mol.64.5.1169}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Peroxisome proliferator-activated receptor-γ (PPAR-γ) has been implicated in the regulation of multiple inflammatory processes. However, little is known of PPAR-γ in the regulation of interleukin (IL)-4 expression in T cells. In this study, the effects of PPAR-γ ligands on production of IL-4, a pro-inflammatory cytokine associated with the pathophysiology of allergic diseases, were investigated. 15-Deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2) and ciglitazone, two representative PPAR-γ 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-γ ligands. In cotransfected EL-4 T cells, PPAR-γ also inhibited the activation of the IL-4 promoter at multiple NF-AT sites in a ligand-dependent manner. NF-ATc1 bound PPAR-γ both in vivo and in vitro, and the interaction interfaces involved the Rel similarity domain of NF-ATc1. In cotransfections of HeLa cells, PPAR-γ inhibited the NF-ATc1 transactivation in a ligand-dependent manner. Coexpression of p300 or AP-1 relieved the PPAR-γ ligand-mediated inhibition of the NF-AT transactivation. From these results, we propose that PPAR-γ 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-γ.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/64/5/1169}, eprint = {https://molpharm.aspetjournals.org/content/64/5/1169.full.pdf}, journal = {Molecular Pharmacology} }