Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-{alpha} agonists in autoimmune disease.
Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPARalpha agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPARalpha expression. Moreover, the protective effects of PPARalpha agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPARalpha was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPARalpha can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPARalpha agonists ameliorated clinically established EAE, suggesting that PPARalpha agonists may provide a treatment option for immune-mediated inflammatory diseases.
Gocke
Anne R
AR
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Hussain
Rehana Z
RZ
Yang
Yuhong
Y
Peng
Haiyan
H
Weiner
Jeffrey
J
Ben
Li-Hong
LH
Drew
Paul D
PD
Stuve
Olaf
O
Lovett-Racke
Amy E
AE
Racke
Michael K
MK
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D011345:Fenofibrate / Q000494:pharmacology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000187:drug effects; D015248:Gemfibrozil / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D000098815:T-bet Transcription Factor
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007155:Immunologic Factors; D015848:Interleukin-5; D047493:PPAR alpha; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D015248:Gemfibrozil; D011345:Fenofibrate