Activation of Human T Lymphocytes Is Inhibited by Peroxisome Proliferator-activated Receptor γ (PPARγ) Agonists

Yang, Xiao Yi; Wang, Li Hua; Chen, Taosheng; Hodge, David R.; Resau, James H.; DaSilva, Luis; Farrar, William L.

doi:10.1074/jbc.275.7.4541

Cited by 366 publications

(287 citation statements)

References 17 publications

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“…Moreover, administration of PPAR␥ ligands is reported to attenuate inflammation in murine models of inflammatory bowel disease (18), nonobese diabetic mice (19), rodent models of atherosclerosis (20 -22) and experimental allergic encephalomyelitis (EAE) (23,24). Studies performed in lymphocyte subpopulations have also confirmed the anti-inflammatory actions of the PPAR ligands (11,25).…”

mentioning

confidence: 70%

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Cunard

DiCampli

Archer

et al. 2002

The Journal of Immunology

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARα and PPARγ are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARα ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARα ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35–55 (pMOG35–55), following immunization with pMOG35–55/CFA. Following in vitro restimulation with pMOG35–55, splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-γ, IL-6, and TNF-α despite similar proliferative responses. We also demonstrate higher expression of PPARα in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARα-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

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mentioning

confidence: 70%

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Cunard

DiCampli

Archer

et al. 2002

The Journal of Immunology

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“…PPAR expression changes with T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Interestingly, PPARγ negatively regulates T-cell activation following TCR stimulation by inhibiting nuclear factor of activated T-cells (NFAT) and subsequent IL-2 production (Clark et al, 2000;Yang et al, 2000). Treatment of mouse T cells with 15d-PGJ2 or ciglitazone inhibited IL-2 production induced by CD3 stimulation (Clark et al, 2000).…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

“…Treatment of mouse T cells with 15d-PGJ2 or ciglitazone inhibited IL-2 production induced by CD3 stimulation (Clark et al, 2000). Likewise, human T cells showed reduced IL-2 production and proliferation upon phytohaemaglutinin (PHA) stimulation in the presence of these PPARγ ligands (Yang et al, 2000). Rosiglitazone treatment of mouse splenocytes decreased phorbol 12-myristate 13-acetate (PMA) and ionomycin-induced interferon-gamma (IFN-γ) production.…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

139

103

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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“…Upon ligand binding, PPAR␥ heterodimerizes with the retinoid X receptor and binds to PPAR response elements located in the promoter region of target genes. Additionally, important antiinflammatory effects of PPAR␥ are mediated by negative interference with proinflammatory cell signaling, either via competition for coactivators or via transrepression through physical interaction with proinflammatory transcription factors, in particular NF-B (9,10). PPAR␥ agonists include endogenous ligands such as polyunsaturated fatty acids and prostanoids like the PGD 2 metabolite 15-deoxy-⌬ (11, 12) PGJ 2 , as well as several synthetic ligands such as the antidiabetic thiazolidinediones, e.g., pioglitazone (PIO) and rosiglitazone, which are currently being used for the correction of metabolic disturbances in type II diabetes (13).…”

mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy

Klotz

Dani

Edenhofer

et al. 2007

The Journal of Immunology

108

110

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There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is a negative regulator of DC maturation and function. Sustained PPARγ activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4+ T cells in vitro. Using PPARγ-deficient DCs, generated by Cre-mediated ablation of the PPARγ gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPARγ increased DC immunogenicity, suggesting a constitutive regulatory function of PPARγ in DCs. Adoptive transfer of PPARγ-activated Ag-presenting DCs induced CD4+ T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPARγ is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4+ T cell-mediated immune responses.

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Activation of Human T Lymphocytes Is Inhibited by Peroxisome Proliferator-activated Receptor γ (PPARγ) Agonists

Abstract: T lymphocyte activation is highlighted by the induction of interleukin-2 (IL-2

Cited by 366 publications

References 17 publications

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Peroxisome Proliferator-Activated Receptor γ Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy

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