Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease

Lovett-Racke, Amy E.; Hussain, Rehana Z.; Northrop, Sara C.; Choy, Judy; Rocchini, Anne; Matthes, Lela; Chavis, Janet A.; Diab, Asim; Drew, Paul D.; Racke, Michael K.

doi:10.4049/jimmunol.172.9.5790

Cited by 200 publications

(179 citation statements)

References 44 publications

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“…PPAR-γ ligands also suppress inflammation and pathology in animal models of atherosclerosis, arthritis, inflammatory bowel disease and MS (Diab et al, 2002;Feinstein et al, 2002;Kawahito et al, 2000;Li et al, 2000;Natarajan and Bright, 2002;Niino et al, 2001;Su et al, 1999). Like PPAR-γ agonists, PPAR-α agonists suppress the function of T cells and CNS glia in vitro (Lovett-Racke et al, 2004;Xu et al, 2006a;Xu et al, 2005b). In addition, these agonists are effective in the treatment of EAE (Lovett-Racke et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Like PPAR-γ agonists, PPAR-α agonists suppress the function of T cells and CNS glia in vitro (Lovett-Racke et al, 2004;Xu et al, 2006a;Xu et al, 2005b). In addition, these agonists are effective in the treatment of EAE (Lovett-Racke et al, 2004). Relatively little is known concerning the role of LXR agonists in modulating inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, RXRs also physically interact with PPAR ligands. We have previously demonstrated that PPAR and RXR ligands act cooperatively in suppressing inflammatory responses (Lovett-Racke et al, 2004;Xu et al, 2006a;Xu et al, 2005b). Future studies will compare the profile of genes regulated by PPAR relative to LXR agonists.…”

Section: Discussionmentioning

confidence: 99%

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Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

Zhang-Gandhi

Drew

2007

Journal of Neuroimmunology

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Liver X receptors (LXRs) are nuclear receptors previously identified to be important in lipid metabolism. Recent reports suggest that LXR agonists also exhibit anti-inflammatory properties in mouse models of atherosclerosis and contact dermatitis. In the present study, we investigated the effects of LXR agonists on mouse microglia and astrocytes. When chronically activated, these resident-CNS glia have been implicated in the pathology of neuroinflammatory disorders including multiple sclerosis (MS). Our studies demonstrated for the first time that LXR agonists inhibited the production of nitric oxide, the pro-inflammatory cytokines IL-1β and IL-6 and the chemokine MCP-1 from LPS-stimulated microglia and astrocytes. Furthermore, LXR agonists inhibited LPS-induction of nuclear factor-kappa B (NF-κB) DNA-binding activity. These agonists also blocked LPSinduction of IκB-α protein degradation in microglia, suggesting a mechanism by which these agonists modulate NF-κB DNA-binding activity. These studies suggest that LXR agonists suppress the production of pro-inflammatory molecules by CNS glia, at least in part, by modulating NF-κB-signaling pathways. Retinoid X receptors (RXRs) physically interact with LXR receptors, and the resulting obligate heterodimer regulates the expression of LXR-responsive genes. Interestingly, a combination of LXR and RXR agonists additively suppressed the production of NO by microglia and astrocytes. Collectively, these studies suggest that LXR agonists may be effective in the treatment of neuroinflammatory diseases including MS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

Zhang-Gandhi

Drew

2007

Journal of Neuroimmunology

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“…IFN-␥ and IL-4 ELISA were performed as previously described (16). IL-17 ELISA was performed using the mouse IL-17 DuoSet (R&D Systems).…”

Section: Elisamentioning

confidence: 99%

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Gocke¹,

Cravens²,

Ben³

et al. 2007

The Journal of Immunology

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236

224

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IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-γ-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.

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“…In glial cells, PPARs (a, b, and g) modulate the production of pro-inflammatory mediators (Lovett-Racke et al 2004, Aleshin et al 2009). PPARg agonists were found to inhibit the release of pro-inflammatory cytokines by microglial cells and astrocytes (Storer et al 2005).…”

Section: Mechanisms Of Mc4r-mediated Effectsmentioning

confidence: 99%

Astrocytes: new targets of melanocortin 4 receptor actions

Caruso¹,

Carniglia²,

Durand³

et al. 2013

Journal of Molecular Endocrinology

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Astrocytes exert a wide variety of functions with paramount importance in brain physiology. After injury or infection, astrocytes become reactive and they respond by producing a variety of inflammatory mediators that help maintain brain homeostasis. Loss of astrocyte functions as well as their excessive activation can contribute to disease processes; thus, it is important to modulate reactive astrocyte response. Melanocortins are peptides with well-recognized anti-inflammatory and neuroprotective activity. Although melanocortin efficacy was shown in systemic models of inflammatory disease, mechanisms involved in their effects have not yet been fully elucidated. Central anti-inflammatory effects of melanocortins and their mechanisms are even less well known, and, in particular, the effects of melanocortins in glial cells are poorly understood. Of the five known melanocortin receptors (MCRs), only subtype 4 is present in astrocytes. MC4R has been shown to mediate melanocortin effects on energy homeostasis, reproduction, inflammation, and neuroprotection and, recently, to modulate astrocyte functions. In this review, we will describe MC4R involvement in anti-inflammatory, anorexigenic, and anti-apoptotic effects of melanocortins in the brain. We will highlight MC4R action in astrocytes and discuss their possible mechanisms of action. Melanocortin effects on astrocytes provide a new means of treating inflammation, obesity, and neurodegeneration, making them attractive targets for therapeutic interventions in the CNS.

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Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease

Cited by 200 publications

References 44 publications

Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Astrocytes: new targets of melanocortin 4 receptor actions

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