The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis

Harris, Sarah G.; Phipps, Richard P.

doi:10.1002/1521-4141(200104)31:4<1098::aid-immu1098>3.0.co;2-i

Cited by 184 publications

(147 citation statements)

References 32 publications

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“…PPAR-␥ protein expression increases as T cells transit from resting to activated state. Initial studies demonstrated that PPAR-␥ activation by synthetic ligands induces lymphocyte apoptosis (25). However, apoptosis occurred at high doses of synthetic agonist, which are generally recognized to be cytotoxic and exert PPAR-␥-independent effects in immune cells (47).…”

Section: Discussionmentioning

confidence: 99%

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Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

Hontecillas

Bassaganya‐Riera

2007

The Journal of Immunology

144

141

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Peroxisome proliferator-activated receptor (PPAR) γ 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-γ remain unclear. We have used PPAR-γ-deficient CD4+ T cells obtained from tissue-specific PPAR-γ null mice (i.e., PPAR-γ fl/fl; MMTV-Cre+) to investigate the role of endogenous PPAR-γ on regulatory T cell (Treg) and effector CD4+ T cell function. Overall, we show that the loss of PPAR-γ results in enhanced Ag-specific proliferation and overproduction of IFN-γ in response to IL-12. These findings correlate in vivo with enhanced susceptibility of tissue-specific PPAR-γ null mice to trinitrobenzene sulfonic acid-induced colitis. Furthermore, the transfer of purified PPAR-γ null CD4+ T cells into SCID recipients results in enteric disease. To test the assertion that the deficiency of PPAR-γ in Treg impairs their ability to prevent effector T cell-induced colitis, we performed cotransfer studies. These studies demonstrate that PPAR-γ-expressing, but not PPAR-γ null Treg, prevent colitis induced by transfer of naive CD4+ T cells into SCID recipients. In line with these findings, the production of IFN-γ by spleen and mesenteric lymph node-derived CD4+ T cells was down-regulated following transfer of PPAR-γ-expressing, but not PPAR-γ null, Treg. In conclusion, our 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.

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Section: Discussionmentioning

confidence: 99%

“…In vitro treatment of splenocytes or fractionated CD4 ϩ T cells with 15-deoxy-PGJ2 and TZD significantly reduces Ag and mitogen-induced proliferation (24,25). PPAR-␥ activation also regulates cytokine secretion by CD4 ϩ T cells (26).…”

mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

Hontecillas

Bassaganya‐Riera

2007

The Journal of Immunology

144

141

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“…One study demonstrated that treatment with high doses of TZDs enhanced T-cell apoptosis (Harris and Phipps, 2001). However, PPARγ activation also resulted in increased survival under conditions of cytokine withdrawal or serum starvation (Jo et al, 2006;Wang et al, 2002).…”

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

149

111

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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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“…Elimination of autoreactive T cells by apoptosis protects CNS tissue from immune-mediated destruction and likely contributes to the resolution of disease (reviewed in [39]). Interestingly, PPAR-γ ligands have been demonstrated to be capable of inducing T-cell apoptosis [19,20], suggesting that these agonists may facilitate the resolution of T-cell-mediated autoimmune diseases. The role of B cells in modulating MS is becoming more appreciated.…”

Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses.Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-α that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS.Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ 2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ 2 is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ 2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ 2 and 9-cis RA inhibit cell activation through the formation of PPAR-γ/ RXR heterodimers. Interestingly, PGA 2 , which like 15d-PGJ 2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ 2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ 2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ 2 in combination with retinoids may be effective in the treatment of MS.

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The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis

Cited by 184 publications

References 32 publications

Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

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

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

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