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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 was more abundant in male as compared with female T cells and was associated with decreased NF-κB and c-jun activity and increased IFN-γ production. (A) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of male and female SV.129 mice (n = 4 mice/group). 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 PPARα/β-actin product abundance in triplicate reactions expressed in arbitrary units (AU). (B) Western blot analysis of PPARα in nuclear extracts (250 μg) prepared from male and female T cells. Histone H3 was used as a loading control. (C) c-jun (left) and NF-κB (right) DNA binding was measured in nuclear extracts from male and female SV.129 WT or PPARα−/− CD3+ T cells using an ELISA-based assay. Nuclear extracts were prepared from T cells at 16 h after stimulation with 5 μg/ml anti-CD3 and 5 μg/ml anti-CD28. Values are means ± SEM of absorbance units (duplicate culture wells) of stimulated wells expressed relative to absorbance in nonstimulated control wells. (D) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 0–2 μg/ml anti-CD3 (left) and 0–5 μg/ml anti-CD28 (right). IFN-γ production in culture supernatants was measured by ELISA at 72 h after stimulation. Values are means ± SEM of triplicate culture wells. Note that anti-CD28 and anti-CD3 were held constant at 0.5 μg/ml in the left and right panels, respectively. Results in A–D are representative of two independent experiments.
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fig4: PPARα was more abundant in male as compared with female T cells and was associated with decreased NF-κB and c-jun activity and increased IFN-γ production. (A) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of male and female SV.129 mice (n = 4 mice/group). 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 PPARα/β-actin product abundance in triplicate reactions expressed in arbitrary units (AU). (B) Western blot analysis of PPARα in nuclear extracts (250 μg) prepared from male and female T cells. Histone H3 was used as a loading control. (C) c-jun (left) and NF-κB (right) DNA binding was measured in nuclear extracts from male and female SV.129 WT or PPARα−/− CD3+ T cells using an ELISA-based assay. Nuclear extracts were prepared from T cells at 16 h after stimulation with 5 μg/ml anti-CD3 and 5 μg/ml anti-CD28. Values are means ± SEM of absorbance units (duplicate culture wells) of stimulated wells expressed relative to absorbance in nonstimulated control wells. (D) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 0–2 μg/ml anti-CD3 (left) and 0–5 μg/ml anti-CD28 (right). IFN-γ production in culture supernatants was measured by ELISA at 72 h after stimulation. Values are means ± SEM of triplicate culture wells. Note that anti-CD28 and anti-CD3 were held constant at 0.5 μg/ml in the left and right panels, respectively. Results in A–D are representative of two independent experiments.

Mentions: In light of reports of gender differences in hepatic PPARα expression (30), we investigated whether the selective influence of PPARα on the functioning of male T cells is due to higher levels of expression of this nuclear receptor. Consistent with this notion, we found that PPARα mRNA expression was higher in male as compared with female CD4+ cells derived from SV.129 (Fig. 4 A), C57/B6, or SJL/J mice (Fig. S1, A and B, available at http://www.jem.org/cgi/content/full/jem.20061839/DC1). This trend for higher male expression was also evident at the protein level as detected via Western blot analysis of nuclear extracts from naive T cells (Fig. 4 B). Compared with the situation in naive T cells, gender differences in PPARα mRNA expression were not as striking in CD4+ cells at 48 h after stimulation with anti-CD3 and anti-CD28 (Fig. S1 C). The latter finding suggests that PPARα may mediate the gender dichotomy in Th1↔Th2 differentiation by influencing T cell responses in the early period after antigen encounter.


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 was more abundant in male as compared with female T cells and was associated with decreased NF-κB and c-jun activity and increased IFN-γ production. (A) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of male and female SV.129 mice (n = 4 mice/group). 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 PPARα/β-actin product abundance in triplicate reactions expressed in arbitrary units (AU). (B) Western blot analysis of PPARα in nuclear extracts (250 μg) prepared from male and female T cells. Histone H3 was used as a loading control. (C) c-jun (left) and NF-κB (right) DNA binding was measured in nuclear extracts from male and female SV.129 WT or PPARα−/− CD3+ T cells using an ELISA-based assay. Nuclear extracts were prepared from T cells at 16 h after stimulation with 5 μg/ml anti-CD3 and 5 μg/ml anti-CD28. Values are means ± SEM of absorbance units (duplicate culture wells) of stimulated wells expressed relative to absorbance in nonstimulated control wells. (D) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 0–2 μg/ml anti-CD3 (left) and 0–5 μg/ml anti-CD28 (right). IFN-γ production in culture supernatants was measured by ELISA at 72 h after stimulation. Values are means ± SEM of triplicate culture wells. Note that anti-CD28 and anti-CD3 were held constant at 0.5 μg/ml in the left and right panels, respectively. Results in A–D are representative of two independent experiments.
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fig4: PPARα was more abundant in male as compared with female T cells and was associated with decreased NF-κB and c-jun activity and increased IFN-γ production. (A) Total RNA was obtained from naive CD4+ T cells that were pooled from the spleens of male and female SV.129 mice (n = 4 mice/group). 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 PPARα/β-actin product abundance in triplicate reactions expressed in arbitrary units (AU). (B) Western blot analysis of PPARα in nuclear extracts (250 μg) prepared from male and female T cells. Histone H3 was used as a loading control. (C) c-jun (left) and NF-κB (right) DNA binding was measured in nuclear extracts from male and female SV.129 WT or PPARα−/− CD3+ T cells using an ELISA-based assay. Nuclear extracts were prepared from T cells at 16 h after stimulation with 5 μg/ml anti-CD3 and 5 μg/ml anti-CD28. Values are means ± SEM of absorbance units (duplicate culture wells) of stimulated wells expressed relative to absorbance in nonstimulated control wells. (D) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 0–2 μg/ml anti-CD3 (left) and 0–5 μg/ml anti-CD28 (right). IFN-γ production in culture supernatants was measured by ELISA at 72 h after stimulation. Values are means ± SEM of triplicate culture wells. Note that anti-CD28 and anti-CD3 were held constant at 0.5 μg/ml in the left and right panels, respectively. Results in A–D are representative of two independent experiments.
Mentions: In light of reports of gender differences in hepatic PPARα expression (30), we investigated whether the selective influence of PPARα on the functioning of male T cells is due to higher levels of expression of this nuclear receptor. Consistent with this notion, we found that PPARα mRNA expression was higher in male as compared with female CD4+ cells derived from SV.129 (Fig. 4 A), C57/B6, or SJL/J mice (Fig. S1, A and B, available at http://www.jem.org/cgi/content/full/jem.20061839/DC1). This trend for higher male expression was also evident at the protein level as detected via Western blot analysis of nuclear extracts from naive T cells (Fig. 4 B). Compared with the situation in naive T cells, gender differences in PPARα mRNA expression were not as striking in CD4+ cells at 48 h after stimulation with anti-CD3 and anti-CD28 (Fig. S1 C). The latter finding suggests that PPARα may mediate the gender dichotomy in Th1↔Th2 differentiation by influencing T cell responses in the early period after antigen encounter.

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