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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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Male PPARα−/− mice developed more severe clinical signs and displayed increased numbers of inflammatory brain lesions in the acute phase of EAE. Male and female WT or PPARα−/− SV.129 mice (n = 8–10/group) were immunized with MOG p35-55 in CFA and given intravenous injections of pertussis toxin on days 0 and 2 after immunization. (A and B) Mean + SEM clinical scores of mice in the different groups at various times after immunization. Shown are results of two independent EAE experiments. * indicates a significant difference from WT group (P < 0.05) as determined using a Mann-Whitney U statistic. (C) Paraffin-embedded sections of brain stem and cerebellum from representative male WT and PPARα−/− mice (from experiment no. 2) during the acute phase of EAE stained with hematoxylin and eosin. Bar in the bottom right, 50 μM.
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fig1: Male PPARα−/− mice developed more severe clinical signs and displayed increased numbers of inflammatory brain lesions in the acute phase of EAE. Male and female WT or PPARα−/− SV.129 mice (n = 8–10/group) were immunized with MOG p35-55 in CFA and given intravenous injections of pertussis toxin on days 0 and 2 after immunization. (A and B) Mean + SEM clinical scores of mice in the different groups at various times after immunization. Shown are results of two independent EAE experiments. * indicates a significant difference from WT group (P < 0.05) as determined using a Mann-Whitney U statistic. (C) Paraffin-embedded sections of brain stem and cerebellum from representative male WT and PPARα−/− mice (from experiment no. 2) during the acute phase of EAE stained with hematoxylin and eosin. Bar in the bottom right, 50 μM.

Mentions: It has been reported that PPARα has a more prominent role in regulating lipid metabolism in male rodents (30–33). To investigate whether the gender dimorphism in PPARα function also extends to antiinflammatory activities of this receptor, we compared the clinical course of EAE in male and female WT versus PPARα−/− mice. EAE was induced in these mice (SV.129 strain, H2b) via immunization with a peptide encoding amino acids 35–55 of myelin oligodendrocyte glycoprotein (MOG p35-55) in CFA. We found in two separate experiments that male PPARα−/− mice displayed a more severe clinical course of EAE compared with WT counterparts, particularly in the acute phase of disease (Fig. 1, A and B, and Table I). Although disease appeared more chronic in male PPARα−/− mice in Fig. 1 A, it is because half of the mice died in the acute phase and were given a clinical score of 5 for the remaining days of the experiment. In contrast to findings for males, the severity of EAE in PPARα−/− females was almost indistinguishable from WT counterparts (Fig. 1, A and B, and Table I). Analysis of the histological features of EAE in male mice revealed that compared with WT, PPARα−/− mice showed higher numbers of parenchymal inflammatory foci in the cerebellum and brainstem in the acute phase of EAE (Fig. 1 C and Table I).


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)

Male PPARα−/− mice developed more severe clinical signs and displayed increased numbers of inflammatory brain lesions in the acute phase of EAE. Male and female WT or PPARα−/− SV.129 mice (n = 8–10/group) were immunized with MOG p35-55 in CFA and given intravenous injections of pertussis toxin on days 0 and 2 after immunization. (A and B) Mean + SEM clinical scores of mice in the different groups at various times after immunization. Shown are results of two independent EAE experiments. * indicates a significant difference from WT group (P < 0.05) as determined using a Mann-Whitney U statistic. (C) Paraffin-embedded sections of brain stem and cerebellum from representative male WT and PPARα−/− mice (from experiment no. 2) during the acute phase of EAE stained with hematoxylin and eosin. Bar in the bottom right, 50 μM.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2118721&req=5

fig1: Male PPARα−/− mice developed more severe clinical signs and displayed increased numbers of inflammatory brain lesions in the acute phase of EAE. Male and female WT or PPARα−/− SV.129 mice (n = 8–10/group) were immunized with MOG p35-55 in CFA and given intravenous injections of pertussis toxin on days 0 and 2 after immunization. (A and B) Mean + SEM clinical scores of mice in the different groups at various times after immunization. Shown are results of two independent EAE experiments. * indicates a significant difference from WT group (P < 0.05) as determined using a Mann-Whitney U statistic. (C) Paraffin-embedded sections of brain stem and cerebellum from representative male WT and PPARα−/− mice (from experiment no. 2) during the acute phase of EAE stained with hematoxylin and eosin. Bar in the bottom right, 50 μM.
Mentions: It has been reported that PPARα has a more prominent role in regulating lipid metabolism in male rodents (30–33). To investigate whether the gender dimorphism in PPARα function also extends to antiinflammatory activities of this receptor, we compared the clinical course of EAE in male and female WT versus PPARα−/− mice. EAE was induced in these mice (SV.129 strain, H2b) via immunization with a peptide encoding amino acids 35–55 of myelin oligodendrocyte glycoprotein (MOG p35-55) in CFA. We found in two separate experiments that male PPARα−/− mice displayed a more severe clinical course of EAE compared with WT counterparts, particularly in the acute phase of disease (Fig. 1, A and B, and Table I). Although disease appeared more chronic in male PPARα−/− mice in Fig. 1 A, it is because half of the mice died in the acute phase and were given a clinical score of 5 for the remaining days of the experiment. In contrast to findings for males, the severity of EAE in PPARα−/− females was almost indistinguishable from WT counterparts (Fig. 1, A and B, and Table I). Analysis of the histological features of EAE in male mice revealed that compared with WT, PPARα−/− mice showed higher numbers of parenchymal inflammatory foci in the cerebellum and brainstem in the acute phase of EAE (Fig. 1 C and Table I).

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