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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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T cells from male PPARα−/− mice were hyperresponsive to TCR stimulation and caused an earlier onset of EAE. (A) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 1 μg/ml anti-CD3 and anti-CD28. The proliferation rate was determined by [3H]thymidine incorporation (cpms), and cytokine production was measured in culture supernatants by ELISA at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10 and IL-4) after stimulation. Values are means ± SEM of triplicate culture wells. * indicates a significant difference (P < 0.05) from WT counterpart. Results are representative of at least three independent experiments. (B) Naive CD4+ T cells from male and female WT and PPARα−/− mice were adoptively transferred into syngeneic male or female RAG2−/− mice by intravenous injection, and EAE was induced in recipient mice 2 d later via immunization with MOG p35-55 in CFA. Mean clinical scores of mice in the different groups at various times after immunization are shown. Results are representative of two independent experiments. * indicates a significant difference from WT (P < 0.05).
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fig3: T cells from male PPARα−/− mice were hyperresponsive to TCR stimulation and caused an earlier onset of EAE. (A) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 1 μg/ml anti-CD3 and anti-CD28. The proliferation rate was determined by [3H]thymidine incorporation (cpms), and cytokine production was measured in culture supernatants by ELISA at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10 and IL-4) after stimulation. Values are means ± SEM of triplicate culture wells. * indicates a significant difference (P < 0.05) from WT counterpart. Results are representative of at least three independent experiments. (B) Naive CD4+ T cells from male and female WT and PPARα−/− mice were adoptively transferred into syngeneic male or female RAG2−/− mice by intravenous injection, and EAE was induced in recipient mice 2 d later via immunization with MOG p35-55 in CFA. Mean clinical scores of mice in the different groups at various times after immunization are shown. Results are representative of two independent experiments. * indicates a significant difference from WT (P < 0.05).

Mentions: PPARα is expressed in T and B lymphocytes (27) and is detected at low levels in peritoneal macrophages and immature dendritic cells (34). To examine whether the enhanced Th1-mediated autoimmunity in male PPARα−/− mice was a result of intrinsic differences in these immune populations, we purified CD3+ T cells, B cells, and macrophages from male and female WT and PPARα−/− mice and compared the activation responses of these cells ex vivo. Consistent with previous reports (26), we found that female WT CD3+ cells proliferated more robustly and secreted higher levels of IFN-γ and TNF and lower amounts of Th2 cytokines (IL-4 and IL-10) as compared with male WT CD3+ cells in response to anti-CD3 and anti-CD28 costimulation (Fig. 3 A). Female CD3+ cells also produced higher levels of IL-17. On the other hand, male and female PPARα−/− T cells displayed similar activation characteristics that more closely resembled the Th1 profile of female WT cells (Fig. 3 A), with the exception that IL-17 production remained low in PPARα−/− male cells. Similar results were observed using CD4+-purified cells (not depicted). Notably, we did not observe major sex differences in the LPS- or IgM-elicited responses of purified B cells or LPS- or IFN-γ–elicited responses of peritoneal macrophages derived from WT or PPARα−/− mice (not depicted), thus indicating that intrinsic differences in T cells are likely responsible for the enhanced Th1 autoimmunity observed in male PPARα−/− mice.


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)

T cells from male PPARα−/− mice were hyperresponsive to TCR stimulation and caused an earlier onset of EAE. (A) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 1 μg/ml anti-CD3 and anti-CD28. The proliferation rate was determined by [3H]thymidine incorporation (cpms), and cytokine production was measured in culture supernatants by ELISA at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10 and IL-4) after stimulation. Values are means ± SEM of triplicate culture wells. * indicates a significant difference (P < 0.05) from WT counterpart. Results are representative of at least three independent experiments. (B) Naive CD4+ T cells from male and female WT and PPARα−/− mice were adoptively transferred into syngeneic male or female RAG2−/− mice by intravenous injection, and EAE was induced in recipient mice 2 d later via immunization with MOG p35-55 in CFA. Mean clinical scores of mice in the different groups at various times after immunization are shown. Results are representative of two independent experiments. * indicates a significant difference from WT (P < 0.05).
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fig3: T cells from male PPARα−/− mice were hyperresponsive to TCR stimulation and caused an earlier onset of EAE. (A) CD3+ T cells from male and female SV.129 WT or PPARα−/− mice were stimulated with 1 μg/ml anti-CD3 and anti-CD28. The proliferation rate was determined by [3H]thymidine incorporation (cpms), and cytokine production was measured in culture supernatants by ELISA at 48 (IL-2), 72 (IFN-γ, TNF, and IL-17), and 120 h (IL-10 and IL-4) after stimulation. Values are means ± SEM of triplicate culture wells. * indicates a significant difference (P < 0.05) from WT counterpart. Results are representative of at least three independent experiments. (B) Naive CD4+ T cells from male and female WT and PPARα−/− mice were adoptively transferred into syngeneic male or female RAG2−/− mice by intravenous injection, and EAE was induced in recipient mice 2 d later via immunization with MOG p35-55 in CFA. Mean clinical scores of mice in the different groups at various times after immunization are shown. Results are representative of two independent experiments. * indicates a significant difference from WT (P < 0.05).
Mentions: PPARα is expressed in T and B lymphocytes (27) and is detected at low levels in peritoneal macrophages and immature dendritic cells (34). To examine whether the enhanced Th1-mediated autoimmunity in male PPARα−/− mice was a result of intrinsic differences in these immune populations, we purified CD3+ T cells, B cells, and macrophages from male and female WT and PPARα−/− mice and compared the activation responses of these cells ex vivo. Consistent with previous reports (26), we found that female WT CD3+ cells proliferated more robustly and secreted higher levels of IFN-γ and TNF and lower amounts of Th2 cytokines (IL-4 and IL-10) as compared with male WT CD3+ cells in response to anti-CD3 and anti-CD28 costimulation (Fig. 3 A). Female CD3+ cells also produced higher levels of IL-17. On the other hand, male and female PPARα−/− T cells displayed similar activation characteristics that more closely resembled the Th1 profile of female WT cells (Fig. 3 A), with the exception that IL-17 production remained low in PPARα−/− male cells. Similar results were observed using CD4+-purified cells (not depicted). Notably, we did not observe major sex differences in the LPS- or IgM-elicited responses of purified B cells or LPS- or IFN-γ–elicited responses of peritoneal macrophages derived from WT or PPARα−/− mice (not depicted), thus indicating that intrinsic differences in T cells are likely responsible for the enhanced Th1 autoimmunity observed in male PPARα−/− mice.

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