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Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity.

Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S, Crowell A, Loh J, Oksenberg J, Steinman L - J. Exp. Med. (2007)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurological Studies, and 2Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.

ABSTRACT
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.

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PPARα mediates androgen sensitivity of Th responses. (A and B) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of castrated- or sham-operated male (n = 4 mice/group) (A) or placebo or α-DHT pellet-implanted female (n = 4 mice/group) (B) mice. The expression of PPARα mRNA in these cells was measured using real-time RT-PCR, and abundance was expressed relative to β-actin mRNA. Values are means ± SEM of PCR product abundance in arbitrary units (AU). * indicates a significant difference (P < 0.05) from either sham (A) or placebo (B). (C) Correlation of serum testosterone (ng/dL) and T cell PPARα mRNA levels in 10 individual mice that were group housed in two cages. (D) CD3+ T cells from sham or castrated male WT and PPARα−/− mice were isolated at 4 wk after surgery and stimulated with 1 μg/ml anti-CD3 and 0.5 μg/ml anti-CD28. Cytokine secretion by T cells was assessed by ELISA analysis of culture supernatants at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels in triplicate culture wells. * indicates a significant difference (P < 0.05) from sham counterpart.
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fig5: PPARα mediates androgen sensitivity of Th responses. (A and B) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of castrated- or sham-operated male (n = 4 mice/group) (A) or placebo or α-DHT pellet-implanted female (n = 4 mice/group) (B) mice. The expression of PPARα mRNA in these cells was measured using real-time RT-PCR, and abundance was expressed relative to β-actin mRNA. Values are means ± SEM of PCR product abundance in arbitrary units (AU). * indicates a significant difference (P < 0.05) from either sham (A) or placebo (B). (C) Correlation of serum testosterone (ng/dL) and T cell PPARα mRNA levels in 10 individual mice that were group housed in two cages. (D) CD3+ T cells from sham or castrated male WT and PPARα−/− mice were isolated at 4 wk after surgery and stimulated with 1 μg/ml anti-CD3 and 0.5 μg/ml anti-CD28. Cytokine secretion by T cells was assessed by ELISA analysis of culture supernatants at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels in triplicate culture wells. * indicates a significant difference (P < 0.05) from sham counterpart.

Mentions: Given the male bias in PPARα expression in T cells, we next investigated whether this gene is sensitive to androgen levels. We found that castration of male mice, which lowered serum testosterone (0.05 ± 0.01 ng/dL in castrated vs. 6.21 ± 2.91 ng/dL in sham-operated mice), decreased the mRNA levels of PPARα in CD4+ T cells pooled from these mice (Fig. 5 A). On the other hand, implantation of female mice with pellets containing the testosterone metabolite 5α-DHT (5 mg) greatly enhanced the expression of PPARα in CD4+ T cells over levels observed in the placebo-treated group (Fig. 5 B). We also investigated the association between PPARα in T cells and serum testosterone levels in individual male mice (n = 10 mice in two cages). As is typical of group-housed males, several males in the cohort had serum testosterone levels that were ∼10-fold higher than cage mates (Fig. 5 C). Interestingly, these dominant males, as defined by testosterone levels, also displayed the highest transcript levels of PPARα in their T cells (Fig. 5 C). Collectively, these findings suggest that the expression of PPARα in T cells correlates with circulating androgen levels.


Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity.

Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S, Crowell A, Loh J, Oksenberg J, Steinman L - J. Exp. Med. (2007)

PPARα mediates androgen sensitivity of Th responses. (A and B) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of castrated- or sham-operated male (n = 4 mice/group) (A) or placebo or α-DHT pellet-implanted female (n = 4 mice/group) (B) mice. The expression of PPARα mRNA in these cells was measured using real-time RT-PCR, and abundance was expressed relative to β-actin mRNA. Values are means ± SEM of PCR product abundance in arbitrary units (AU). * indicates a significant difference (P < 0.05) from either sham (A) or placebo (B). (C) Correlation of serum testosterone (ng/dL) and T cell PPARα mRNA levels in 10 individual mice that were group housed in two cages. (D) CD3+ T cells from sham or castrated male WT and PPARα−/− mice were isolated at 4 wk after surgery and stimulated with 1 μg/ml anti-CD3 and 0.5 μg/ml anti-CD28. Cytokine secretion by T cells was assessed by ELISA analysis of culture supernatants at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels in triplicate culture wells. * indicates a significant difference (P < 0.05) from sham counterpart.
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fig5: PPARα mediates androgen sensitivity of Th responses. (A and B) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of castrated- or sham-operated male (n = 4 mice/group) (A) or placebo or α-DHT pellet-implanted female (n = 4 mice/group) (B) mice. The expression of PPARα mRNA in these cells was measured using real-time RT-PCR, and abundance was expressed relative to β-actin mRNA. Values are means ± SEM of PCR product abundance in arbitrary units (AU). * indicates a significant difference (P < 0.05) from either sham (A) or placebo (B). (C) Correlation of serum testosterone (ng/dL) and T cell PPARα mRNA levels in 10 individual mice that were group housed in two cages. (D) CD3+ T cells from sham or castrated male WT and PPARα−/− mice were isolated at 4 wk after surgery and stimulated with 1 μg/ml anti-CD3 and 0.5 μg/ml anti-CD28. Cytokine secretion by T cells was assessed by ELISA analysis of culture supernatants at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels in triplicate culture wells. * indicates a significant difference (P < 0.05) from sham counterpart.
Mentions: Given the male bias in PPARα expression in T cells, we next investigated whether this gene is sensitive to androgen levels. We found that castration of male mice, which lowered serum testosterone (0.05 ± 0.01 ng/dL in castrated vs. 6.21 ± 2.91 ng/dL in sham-operated mice), decreased the mRNA levels of PPARα in CD4+ T cells pooled from these mice (Fig. 5 A). On the other hand, implantation of female mice with pellets containing the testosterone metabolite 5α-DHT (5 mg) greatly enhanced the expression of PPARα in CD4+ T cells over levels observed in the placebo-treated group (Fig. 5 B). We also investigated the association between PPARα in T cells and serum testosterone levels in individual male mice (n = 10 mice in two cages). As is typical of group-housed males, several males in the cohort had serum testosterone levels that were ∼10-fold higher than cage mates (Fig. 5 C). Interestingly, these dominant males, as defined by testosterone levels, also displayed the highest transcript levels of PPARα in their T cells (Fig. 5 C). Collectively, these findings suggest that the expression of PPARα in T cells correlates with circulating androgen levels.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurological Studies, and 2Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus