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

Abstract

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.