Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis

Diab, Asim; Deng, Cheng; Smith, Jeff D.; Hussain, Rehana Z.; Phanavanh, Bounleut; Lovett-Racke, Amy E.; Drew, Paul D.; Racke, Michael K.

doi:10.4049/jimmunol.168.5.2508

Cited by 278 publications

(241 citation statements)

References 39 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: 66%

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: 66%

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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“…This PPAR-γ agonist also suppressed IFN-γ, IL-10, and IL-4 production by activated lymphocytes [12]. Administration of 15d-PGJ 2 at the onset of clinical disease significantly reduced EAE severity, supporting the potential clinical relevance of this treatment paradigm [12]. Feinstein et al [16] demonstrated that oral administration of thiazolidinediones including pioglitazone reduced the clinical severity of monophasic EAE, but it did not delay disease onset.…”

Section: Ppar-γ: Role In Eaementioning

confidence: 98%

“…Evidence to suggest that PPAR-γ agonists may potentially ameliorate MS was initially provided by Niino et al [36] who demonstrated that troglitazone inhibited the development of EAE. Diab et al [12] reported that the PPAR-γ agonist 15d-PGJ 2 inhibited the proliferation of neural antigen-specific T cells from the spleen of myelin basic protein Ac 1-11 TCR-transgenic mice, which spontaneously develop EAE. This PPAR-γ agonist also suppressed IFN-γ, IL-10, and IL-4 production by activated lymphocytes [12].…”

Section: Ppar-γ: Role In Eaementioning

confidence: 99%

“…Diab et al [12] reported that the PPAR-γ agonist 15d-PGJ 2 inhibited the proliferation of neural antigen-specific T cells from the spleen of myelin basic protein Ac 1-11 TCR-transgenic mice, which spontaneously develop EAE. This PPAR-γ agonist also suppressed IFN-γ, IL-10, and IL-4 production by activated lymphocytes [12]. Administration of 15d-PGJ 2 at the onset of clinical disease significantly reduced EAE severity, supporting the potential clinical relevance of this treatment paradigm [12].…”

Section: Ppar-γ: Role In Eaementioning

confidence: 99%

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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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“…Repression of fas-L expression in activated T cells might act in combination with the various effects mediated by 15d-PGJ 2 at the inflammatory site, in particular at the onset of autoimmune diseases in which local inflammation and tissue injury mediated by Th1 cytokines and Fas-L-mediated killing can generate specific tissue and organ damage. The recent description of in vivo studies that reveal a role for 15d-PGJ 2 as a molecule that may ameliorate inflammation in diseases such as EAE or IBD (15,18), together with the role mediated by Fas-L in these kinds of pathologies (23,71), suggest that modulation of this gene by 15d-PGJ 2 in T cells may represent an additional tool to consider for treatment of specific autoimmune and inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

The Cyclopentenone-Type Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanisms

Cippitelli

Fionda

Bona

et al. 2003

The Journal of Immunology

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15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. 15d-PGJ2 is a natural ligand of the peroxisome proliferator-activated receptor (PPAR)-γ nuclear receptor, but relevant PPARγ-independent actions mediated by this prostanoid have been described. Fas (APO-1/CD95) and its ligand (Fas-L) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death and has been implicated in diseases in which lymphocyte homeostasis is compromised. Moreover, several studies have described the pathogenic functions of Fas and Fas-L in vivo, particularly in the induction-progression of organ-specific autoimmune diseases. In this study we describe the effect of 15d-PGJ2 on the activation of the fas-L gene in T lymphocytes. We show that 15d-PGJ2 inhibits fas-L mRNA expression, activation-induced cell death, and fas-L promoter activity by mechanisms independent of PPARγ and mediated by its chemically reactive cyclopentenone moiety. Our data indicate that 15d-PGJ2 may repress fas-L activation by interfering with the expression and/or transcriptional activity of different transcription factors (early growth response types 3 and 1, NF-κB, AP-1, c-Myc, Nur77) whose altered balancing and transactivation may contribute for overall repression of this gene. In addition, the activation/expression of the heat shock response genes HSF-1 and HSP70 is not directly involved in the repression, and the electrophilic molecule cyclopentenone (2-cyclopenten-1-one) may reproduce the effects mediated by 15d-PGJ2. These results suggest that modulation of Fas-L by 15d-PGJ2 in T cells may represent an additional tool to consider for treatment of specific autoimmune and inflammatory disorders.

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Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis

Cited by 278 publications

References 39 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

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

The Cyclopentenone-Type Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor-γ-Independent Mechanisms

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