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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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Splenocytes from MOG-immunized male PPARα−/− mice secreted higher levels of IFN-γ and TNF compared with WT counterparts. Splenocytes from male and female SV.129 WT or PPARα−/− mice were harvested 10 d after EAE induction and stimulated with 0–20 μg/ml MOG p35-55. (A) Proliferation of cells in response to 5 μg/ml MOG peptide was measured by [3H]thymidine incorporation (cpm). Values are means ± SEM counts of radioactivity per minute (cpm) of triplicate culture wells. (B) Cytokine levels in culture supernatants were measured by ELISA at 48 (IL-17), 72 (IFN-γ and TNF), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels (pg/ml) in triplicate culture wells. Note that IL-4 was not detected in culture supernatants. Results are representative of two to three independent experiments.
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fig2: Splenocytes from MOG-immunized male PPARα−/− mice secreted higher levels of IFN-γ and TNF compared with WT counterparts. Splenocytes from male and female SV.129 WT or PPARα−/− mice were harvested 10 d after EAE induction and stimulated with 0–20 μg/ml MOG p35-55. (A) Proliferation of cells in response to 5 μg/ml MOG peptide was measured by [3H]thymidine incorporation (cpm). Values are means ± SEM counts of radioactivity per minute (cpm) of triplicate culture wells. (B) Cytokine levels in culture supernatants were measured by ELISA at 48 (IL-17), 72 (IFN-γ and TNF), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels (pg/ml) in triplicate culture wells. Note that IL-4 was not detected in culture supernatants. Results are representative of two to three independent experiments.

Mentions: There appeared to be an immune basis for the more severe clinical phenotype in male PPARα−/− mice because MOG p35-55–reactive splenocytes from these mice proliferated more robustly (Fig. 2 A, left) and secreted higher levels of Th1 cytokines, such as IFN-γ and TNF, and lower levels of the antiinflammatory cytokine IL-10 (Fig. 2 B, left) compared with male WT splenocytes. Interestingly, the absence of PPARα in male splenocytes also resulted in lower production of IL-17 (Fig. 2 A, left). On the other hand, although female PPARα−/− MOG p35-55–reactive splenocytes displayed heightened proliferative responses (Fig. 2 A, right), no major differences in cytokine production were apparent between female WT and PPARα−/− groups (Fig. 2 B, right).


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)

Splenocytes from MOG-immunized male PPARα−/− mice secreted higher levels of IFN-γ and TNF compared with WT counterparts. Splenocytes from male and female SV.129 WT or PPARα−/− mice were harvested 10 d after EAE induction and stimulated with 0–20 μg/ml MOG p35-55. (A) Proliferation of cells in response to 5 μg/ml MOG peptide was measured by [3H]thymidine incorporation (cpm). Values are means ± SEM counts of radioactivity per minute (cpm) of triplicate culture wells. (B) Cytokine levels in culture supernatants were measured by ELISA at 48 (IL-17), 72 (IFN-γ and TNF), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels (pg/ml) in triplicate culture wells. Note that IL-4 was not detected in culture supernatants. Results are representative of two to three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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fig2: Splenocytes from MOG-immunized male PPARα−/− mice secreted higher levels of IFN-γ and TNF compared with WT counterparts. Splenocytes from male and female SV.129 WT or PPARα−/− mice were harvested 10 d after EAE induction and stimulated with 0–20 μg/ml MOG p35-55. (A) Proliferation of cells in response to 5 μg/ml MOG peptide was measured by [3H]thymidine incorporation (cpm). Values are means ± SEM counts of radioactivity per minute (cpm) of triplicate culture wells. (B) Cytokine levels in culture supernatants were measured by ELISA at 48 (IL-17), 72 (IFN-γ and TNF), and 120 h (IL-10) after stimulation. Values are means ± SEM of cytokine levels (pg/ml) in triplicate culture wells. Note that IL-4 was not detected in culture supernatants. Results are representative of two to three independent experiments.
Mentions: There appeared to be an immune basis for the more severe clinical phenotype in male PPARα−/− mice because MOG p35-55–reactive splenocytes from these mice proliferated more robustly (Fig. 2 A, left) and secreted higher levels of Th1 cytokines, such as IFN-γ and TNF, and lower levels of the antiinflammatory cytokine IL-10 (Fig. 2 B, left) compared with male WT splenocytes. Interestingly, the absence of PPARα in male splenocytes also resulted in lower production of IL-17 (Fig. 2 A, left). On the other hand, although female PPARα−/− MOG p35-55–reactive splenocytes displayed heightened proliferative responses (Fig. 2 A, right), no major differences in cytokine production were apparent between female WT and PPARα−/− groups (Fig. 2 B, right).

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