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
. 2012 Jun 12;109(24):9505-10.
doi: 10.1073/pnas.1118458109. Epub 2012 May 30.

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Monan Angela Zhang  1 , Dorothy Rego, Marina Moshkova, Hania Kebir, Andrzej Chruscinski, Hoangkim Nguyen, Rainer Akkermann, Frank Z Stanczyk, Alexandre Prat, Lawrence Steinman, Shannon E Dunn
Affiliations

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Monan Angela Zhang et al. Proc Natl Acad Sci U S A. .

Abstract

Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4(+) T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4(+) T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4(+) T cells. Intriguingly, male CD4(+) T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activated receptor (PPAR)α and PPARγ. Androgens increased PPARα and decreased PPARγ expression by human CD4(+) T cells. PPARα siRNA-mediated knockdown had the effect of increasing IFNγ by male CD4(+) T cells, while transfection of CD4(+) T cells with PPARγ siRNAs increased IL-17A production uniquely by female T cells. Together, our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and IL-17A that may be driven by expressions of PPARα and PPARγ.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
PLP p139-151-reactive CD4+ from female SJL mice produce more IFNγ and proliferate more than male CD4+ cells. (A and B) Male and female SJL mice (8 wk) were immunized with PLP p139-151 in CFA. Eight days later, cells from draining lymph nodes (A) and spleens (B) were harvested, were pooled within groups, and then cultured with PLP p139-151. (C) CD4+ T cells were isolated from nonimmunized male and female mice and were activated with plate-bound anti-CD3 and anti-CD28. Shown are the proliferation and cytokine responses to the various stimuli. In A and B, proliferation values are expressed as a stimulation (Stim.) index: 3[H]thymidine incorporation in peptide-stimulated wells divided by the media control wells. In C, proliferation values are expressed as cpm. In all cases, values are means ± SEM of triplicate cultures. *Significant difference (P ≤ 0.05) from males, as determined using a t test (two-tailed). Results are representative of three experiments.
Fig. 2.
Fig. 2.
Sex difference in cytokine production associates with hormone status in male mice. (A–D) Male SJL/J mice (5 wk old; n = 5/group) were subjected to castration or sham surgery. Three weeks later, mice were immunized with PLP p139-151 in CFA. (A–C) Eight days later, the spleens were collected from mice and were pooled, and cells were stimulated with PLP p139-151. *Significantly different (P ≤ 0.05) from sham using a t test (two-tailed). (D) Mononuclear cells were isolated from the spinal cords of male sham and castrated mice during the acute phase of EAE. Mice were all at score 3 and were sick for an equivalent period. (E–G) WT or PPARα−/− SV.129 female mice (5 wk of age; n = 3/group) were implanted with pellet containing DHT (5 mg) or carrier-binder (placebo). Three weeks later, CD4+ T cells were pooled and then cultured with anti-CD3 and anti-CD28 in RPMI containing with 1% autologous serum. (E) Relative abundance of PPARα mRNA (relative to β-actin) in freshly isolated CD4+ T cells. (F and G) Production of IFNγ (F) and IL-17A (G) in T-cell cultures. *Significantly different (P ≤ 0.05) from placebo counterpart, as determined using a one-way ANOVA and Tukey post hoc test. Values are means ± SEM of measurements in triplicate cultures. Results are representative of two to three experiments.
Fig. 3.
Fig. 3.
CD4+ cells from women are more prone to produce IFNγ and less IL-17A than male T cells. Naïve (CD45RA+) CD4+ T cells were isolated from peripheral blood of healthy men and women (n = 25/group) and were cultured in X-VIVO-15 serum-free media in the presence of anti-CD3- and anti-CD28-coated beads. Supernatants were collected at 72 h poststimulation. T cells were expanded in IL-2 containing X-VIVO-15 media for an additional 7 d before stimulation phorbol myristate acetate (PMA)/ionomycin. (A and D) Absolute IFNγ and IL-17A levels detected in culture supernatants. (B and E) IFNγ and IL-17A mRNAs (expressed relative to β-actin). (C) Frequency of IFNγ-producing T cells. Values are means ± SEM measurements from individual human subjects. (F and G) Difference in IFNγ and IL-17A production (pg/mL) in individual pairs (female minus male value). *Significantly different (P ≤ 0.05) from male, as determined using a paired t test (two-tailed).
Fig. 4.
Fig. 4.
PPARα has a sex-specific role in inhibiting Th1 cytokine production by human T cells. (A) CD4+ T cells were isolated from peripheral blood of healthy men and women (n = 10/group) and were either frozen down or stimulated with anti-CD3 and anti-CD28 for 31 h. PPARα mRNAs were measured using real-time PCR and were normalized to β-actin mRNAs. (B) Relative expression of PPARα mRNAs in stimulated male and female T cells. (C) PPARα mRNA expression by CD4+ T cells of men or women (n = 4/group) after stimulation for 72 h with 100 nM DHT or vehicle. (D) Location of probable AR (boxed) and estrogen receptor (underlined) binding sites in the human and mouse PPARα promoters. (E and F) PBMCs were isolated from women and were cultured in the presence (+) or absence (−) of anti-CD3/anti-CD28, plus (+) 100 nM DHT or vehicle (−). DNA was isolated from cells for ChIP of the PPARα promoter using an anti-AR or isotype control antibody. Representative gels (one donor) (E) and relative abundance of the PCR-amplified product of the PPARα promoter in three female donors post-ChIP (F). (G–I) CD4+ from men and women (n = 10/group) were transfected with a GFP construct, along with either PPARα or nontargeting control siRNAs, before stimulation with anti-CD3 and anti-CD28 for 48 h. (G) Extent of PPARα knockdown. (H) Absolute IFNγ levels detected in CD4+ T-cell cultures after stimulation. (I) Mean percentage increase in IFNγ over nontargeting control siRNA for male (gray bar) and female (black bar) donors. (J) Percentage decrease in IFNγ in cultures after stimulation of T cells of men and women (n = 4 each) with 2.5 µM fenofibrate relative to vehicle (DMSO) control. In all cases, values are means ± SEM of individual human donors. *Significantly different (P ≤ 0.05), as determined using a t test (two-tailed) or a one-way ANOVA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Orton SM, et al. Canadian Collaborative Study Group Sex ratio of multiple sclerosis in Canada: A longitudinal study. Lancet Neurol. 2006;5:932–936. - PubMed
    1. Debouverie M, Pittion-Vouyovitch S, Louis S, Roederer T, Guillemin F. Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France. Mult Scler. 2007;13:962–967. - PubMed
    1. Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994;96:457–462. - PubMed
    1. Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M. Multiple sclerosis in children: Clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 2007;6:887–902. - PubMed
    1. International Multiple Sclerosis Genetics Consortium. Wellcome Trust Case Control Consortium 2 Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in Multiple sclerosis. Nature. 2011. pp. 214–219. - PMC - PubMed

Publication types