Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity.
Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor that mediates gender differences in lipid metabolism. PPARalpha also functions to control inflammatory responses by repressing the activity of nuclear factor kappaB (NF-kappaB) and c-jun in immune cells. Because PPARalpha is situated at the crossroads of gender and immune regulation, we hypothesized that this gene may mediate sex differences in the development of T cell-mediated autoimmune disease. We show that PPARalpha is more abundant in male as compared with female CD4(+) cells and that its expression is sensitive to androgen levels. Genetic ablation of this gene selectively removed the brake on NF-kappaB and c-jun activity in male T lymphocytes, resulting in higher production of interferon gamma and tumor necrosis factor (but not interleukin 17), and lower production of T helper (Th)2 cytokines. Upon induction of experimental autoimmune encephalomyelitis, male but not female PPARalpha(-/-) mice developed more severe clinical signs that were restricted to the acute phase of disease. These results suggest that males are less prone to develop Th1-mediated autoimmunity because they have higher T cell expression of PPARalpha.
Dunn
Shannon E
SE
Department of Neurology and Neurological Studies, and 2Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Ousman
Shalina S
SS
Sobel
Raymond A
RA
Zuniga
Luis
L
Baranzini
Sergio E
SE
Youssef
Sawsan
S
Crowell
Andrea
A
Loh
John
J
Oksenberg
Jorge
J
Steinman
Lawrence
L
D019264:Adoptive Transfer; D000728:Androgens / Q000097:blood / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000728:Androgens; D016207:Cytokines; D017931:DNA Primers; D016328:NF-kappa B; D047493:PPAR alpha; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma