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
01 Nov 2003-Molecular Pharmacology (American Society for Pharmacology and Experimental Therapeutics)-Vol. 64, Iss: 5, pp 1169-1179
TL;DR: It is proposed 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.
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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TL;DR: The role of m TOR in regulating metabolism and how these pathways intersect with the ability of mTOR to integrate cues that guide the outcome of T‐cell receptor engagement are discussed.
Abstract: Upon antigen recognition, naive T cells undergo rapid expansion and activation. The energy requirements for this expansion are formidable, and T-cell activation is accompanied by dramatic changes in cellular metabolism. Furthermore, the outcome of antigen engagement is guided by multiple cues derived from the immune microenvironment. Mammalian target of rapamycin (mTOR) is emerging as a central integrator of these signals playing a critical role in driving T-cell differentiation and function. Indeed, multiple metabolic programs are controlled by mTOR signaling. In this review, we discuss the role of mTOR in regulating metabolism and how these pathways intersect with the ability of mTOR to integrate cues that guide the outcome of T-cell receptor engagement.
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TL;DR: The critical role of the established transcriptional partners and functional outcomes of these NFAT interactions in regard to the effector responses of these clinically relevant CD4(+) T helper subsets are reviewed.
184 citations
Cites background from "Inhibition of Interleukin-4 Product..."
...62-64 PPARγ also inhibits Il4 promoter activation in a ligand-dependent manner at multiple NFAT sites.(65) NFAT and STAT6 activity are also required for the recruitment of the Brahma-related gene-1 (BRG1) catalytic subunit of SWI/SNF-related complexes to the Th2 locus control region, and STAT6 associates with BRG1 in For personal use only....
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TL;DR: The data suggest that endogenous PPAR-γ activation represents a Treg intrinsic mechanism of down-regulation of effector CD4+ T cell function and prevention of colitis.
Abstract: Peroxisome proliferator-activated receptor (PPAR) gamma activation has been implicated in the prevention of immunoinflammatory disorders; however, the mechanisms of regulation of effector and regulatory CD4+ T cell functions by endogenously activated PPAR-gamma remain unclear. We have used PPAR-gamma-deficient CD4+ T cells obtained from tissue-specific PPAR-gamma null mice (i.e., PPAR-gamma fl/fl; MMTV-Cre+) to investigate the role of endogenous PPAR-gamma on regulatory T cell (Treg) and effector CD4+ T cell function. Overall, we show that the loss of PPAR-gamma results in enhanced Ag-specific proliferation and overproduction of IFN-gamma in response to IL-12. These findings correlate in vivo with enhanced susceptibility of tissue-specific PPAR-gamma null mice to trinitrobenzene sulfonic acid-induced colitis. Furthermore, the transfer of purified PPAR-gamma null CD4+ T cells into SCID recipients results in enteric disease. To test the assertion that the deficiency of PPAR-gamma in Treg impairs their ability to prevent effector T cell-induced colitis, we performed cotransfer studies. These studies demonstrate that PPAR-gamma-expressing, but not PPAR-gamma null Treg, prevent colitis induced by transfer of naive CD4+ T cells into SCID recipients. In line with these findings, the production of IFN-gamma by spleen and mesenteric lymph node-derived CD4+ T cells was down-regulated following transfer of PPAR-gamma-expressing, but not PPAR-gamma null, Treg. In conclusion, our data suggest that endogenous PPAR-gamma activation represents a Treg intrinsic mechanism of down-regulation of effector CD4+ T cell function and prevention of colitis.
165 citations
Cites background from "Inhibition of Interleukin-4 Product..."
...Treatment of CD4 T cells with ciglitazone or 15-deoxy-PGJ2 triggered the physical association between PPAR- and NFATc1, resulting in IL-4 promoter inhibition and decreased IL-4 production (28), and 13-hydroxyoctadecadienoic acid (13-HODE) a putative endogenously generated PPAR- agonist, down-regulated IL-2 production by human peripheral blood T lymphocytes by reducing NFAT and NF- B binding to the IL-2 promoter (29)....
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TL;DR: This review addresses the possible reasons for the different roles played by NFAT proteins in cell cycle regulation and apoptosis, particularly regarding N- and C-terminal transactivation regions (TADs) and the partner proteins that interact with these TADs.
Abstract: The NFAT (nuclear factor of activated T cells) family of transcription factors consists of four Ca2+-regulated members (NFAT1–NFAT4), which were first described in T lymphocytes. In addition to their well-documented role in T lymphocytes, where they control gene expression during cell activation and differentiation, NFAT proteins are also expressed in a wide range of cells and tissue types and regulate genes involved in cell cycle, apoptosis, angiogenesis and metastasis. The NFAT proteins share a highly conserved DNA-binding domain (DBD), which allows all NFAT members to bind to the same DNA sequence in enhancers or promoter regions. The same DNA-binding specificity suggests redundant roles for the NFAT proteins, which is true during the regulation of some genes such as IL-2 and p21. However, it has become increasingly clear that different NFAT proteins and even isoforms can have unique functions. In this review, we address the possible reasons for these distinct roles, particularly regarding N- and C-terminal transactivation regions (TADs) and the partner proteins that interact with these TADs. We also discuss the genes regulated by NFAT during cell cycle regulation and apoptosis and the role of NFAT during tumorigenesis.
146 citations
TL;DR: The present article reviews the current knowledge of the role of PPARα and PPARγ in controlling inflammation, and presents different findings suggesting that PPAR α andPPARγ activators may be helpful in the treatment of lung inflammatory diseases.
Abstract: Lung inflammatory diseases, such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis, represent a major health problem worldwide Although glucocorticoids are the most potent anti-inflammatory drug in asthma, they exhibit major side effects and have poor activity in lung inflammatory disorders such as ALI or COPD Therefore, there is growing need for the development of alternative or new therapies to treat inflammation in the lung Peroxisome proliferator-activated receptors (PPARs), including the three isotypes PPARalpha, PPARbeta (or PPARdelta) and PPARgamma, are transcription factors belonging to the nuclear hormone receptor superfamily PPARs, and in particular PPARalpha and PPARgamma, are well known for their critical role in the regulation of energy homeostasis by controlling expression of a variety of genes involved in lipid and carbohydrate metabolism Synthetic ligands of the two receptor isotypes, the fibrates and the thiazolidinediones, are clinically used to treat dyslipidaemia and type 2 diabetes, respectively Recently however, PPARalpha and PPARgamma have been shown to exert a potent anti-inflammatory activity, mainly through their ability to downregulate pro-inflammatory gene expression and inflammatory cell functions The present article reviews the current knowledge of the role of PPARalpha and PPARgamma in controlling inflammation, and presents different findings suggesting that PPARalpha and PPARgamma activators may be helpful in the treatment of lung inflammatory diseases
112 citations
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"Inhibition of Interleukin-4 Product..." refers background in this paper
...IL-4 plays a critical role in regulating the outcome of an immune response by facilitating the differentiation of CD4 T cells into IL-4–producing T helper (Th) type 2 cells and suppressing the differentiation of interferon- (IFN- )producing Th1 cells, thereby favoring humoral immune responses (Abbas et al., 1996)....
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TL;DR: It is reported that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis, and raised the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compounds.
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TL;DR: It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects
3,587 citations
TL;DR: A pivotal role is suggested for PPARγ and its endogenous ligand in adipocyte development and glucose homeostasis and as a target for intervention in metabolic disorders.
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TL;DR: Recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation ofNFAT proteins with other transcription factors to regulate the expression of inducible genes are discussed.
Abstract: As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much attention. NFAT proteins, which are expressed in most immune-system cells, play a pivotal role in the transcription of cytokine genes and other genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a primary target for inhibition by cyclosporin A and FK506. Calcineurin controls the translocation of NFAT proteins from the cytoplasm to the nucleus of activated cells by interacting with an N-terminal regulatory domain conserved in the NFAT family. The DNA-binding domains of NFAT proteins resemble those of Rel-family proteins, and Rel and NFAT proteins show some overlap in their ability to bind to certain regulatory elements in cytokine genes. NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells. This review discusses recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation of NFAT proteins with other transcription factors to regulate the expression of inducible genes.
2,606 citations
"Inhibition of Interleukin-4 Product..." refers background in this paper
...A phase of shortterm gene transcription, elicited by the interaction of differentiated T cells with antigen, requires the antigen-induced transcription factor NF-AT (Rao et al., 1997)....
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