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Peroxisome Proliferator-Activated Receptor- Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia¹

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205

The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)- agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR- agonists, including the naturally occurring 15-deoxy-^12,14-PGJ₂ and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-^12,14-PGJ₂ potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR- agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR- agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR- agonists may be beneficial in the treatment of MS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (NS42860 and NS 047546), the National Multiple Sclerosis Society (RG 3427-A-8), and the Arkansas Biosciences Institute.

² Address correspondence and reprint requests to Dr. Paul D. Drew, University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, Slot 846, Biomedical Research Building II, Room 563-2, 4301 West Markham Street, Little Rock, AR 72205. E-mail address: drewpauld{at}uams.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; EAE, experimental autoimmune encephalomyelitis; EBI3, EBV-induced molecule 3; PAMP, pathogen-associated molecular pattern; PPAR, peroxisome proliferator-activated receptor.

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