Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2007 Feb 19;204(2):321-30.
doi: 10.1084/jem.20061839. Epub 2007 Jan 29.

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

Shannon E Dunn  1 , Shalina S Ousman, Raymond A Sobel, Luis Zuniga, Sergio E Baranzini, Sawsan Youssef, Andrea Crowell, John Loh, Jorge Oksenberg, Lawrence Steinman
Affiliations
Comparative Study

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

Shannon E Dunn et al. J Exp Med. .

Erratum in

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
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.
Figure 2.
Figure 2.
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.
Figure 3.
Figure 3.
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).
Figure 4.
Figure 4.
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.
Figure 5.
Figure 5.
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Steinman, L. 1996. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell. 85:299–302. - PubMed
    1. Noseworthy, J.H., C. Lucchinetti, M. Rodriguez, and B.G. Weinshenker. 2000. Multiple sclerosis. N. Engl. J. Med. 343:938–952. - PubMed
    1. Lock, C., G. Hermans, R. Pedotti, A. Brendolan, E. Schadt, H. Garren, A. Langer-Gould, S. Strober, B. Cannella, J. Allard, et al. 2002. Gene microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8:500–508. - PubMed
    1. Langrish, C.L., Y. Chen, W.M. Blumenschein, J. Mattson, B. Basham, J.D. Sedgwick, T. McClanahan, R.A. Kastelein, and D.J. Cua. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–240. - PMC - PubMed
    1. Komiyama, Y., S. Nakae, T. Matsuki, A. Nambu, H. Ishigame, S. Kakuta, K. Sudo, and Y. Iwakura. 2006. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177:566–573. - PubMed

Publication types

MeSH terms