Peroxisome proliferator-activated receptor-α agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis

• Published in: Journal of neurochemistry 2007-12, Vol.103 (5), p.1801-1810
• Main Authors: Xu, Jihong, Racke, Michael K, Drew, Paul D
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Cerebrospinal fluid. Meninges. Spinal cord; Cytokines - genetics; Cytokines - metabolism; Cytokines - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; experimental autoimmune encephalomyelitis; fenofibrate; Fenofibrate - pharmacology; Gene Expression Regulation - drug effects; glia; interleukin-12; Interleukin-12 - metabolism; interleukin-23; interleukin-27; Lipopolysaccharide Receptors - genetics; Lipopolysaccharide Receptors - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Microglia - drug effects; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Nervous system (semeiology, syndromes); Neurology; Polysaccharides - pharmacology; PPAR alpha - agonists
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04875.x

The interleukin-12 (IL-12) family of cytokines which includes IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Previously, we demonstrated that peroxisome proliferator-activated receptor (PPAR) -α agonists suppress the development of EAE. The present studies demonstrated that the PPAR-α agonist fenofibrate inhibited the secretion of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 by lipopolysaccharide-stimulated microglia. The cytokines interferon-γ and tumor necrosis factor-α also stimulated IL-12 p40 and IL-27 p28 expression by microglia, which was suppressed by fenofibrate. Furthermore, fenofibrate inhibited microglial expression of CD14 which plays a critical role in TLR signaling, suggesting a mechanism by which this PPAR-α agonist regulates the production of these pro-inflammatory molecules. In addition, fenofibrate suppressed the secretion of IL-12p40, IL-23, and IL-27p28 by lipopolysaccharide-stimulated astrocytes. Importantly, fenofibrate suppression of EAE was associated with decreased expression of IL-12 family cytokine mRNAs as well as mRNAs encoding TLR4, CD14, and MyD88 known to play critical roles in MyD88-dependent TLR signaling. These novel observations suggest that PPAR-α agonists including fenofibrate may modulate the development of EAE, at least in part, by suppressing the production of IL-12 family cytokines and MyD88-dependent signaling.