Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Gourdy, Pierre; Araujo, Luiza M.; Zhu, Rong; Garmy‐Susini, Barbara; Diem, Séverine; Laurell, Henrik; Leite‐de‐Moraes, Maria; Dy, Michel; Arnal, Jean‐François; Bayard, Françis; Herbelin, André

doi:10.1182/blood-2004-07-2819

Cited by 136 publications

(78 citation statements)

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“…This apparent discrepancy between physiological and supraestrus levels of E 2 was previously reported by our group in other extrareproductive effects, such as atherosclerosis prevention (10) and modulation of invariant natural killer T cells (11).…”

Section: Discussionmentioning

confidence: 59%

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Gamé¹,

Allard²,

Escourrou³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Gamé X, Allard J, Escourrou G, Gourdy P, Tack I, Rischmann P, Arnal J-F, Malavaud B. Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression. Am J Physiol Regul Integr Comp Physiol 294: R851-R857, 2008. First published January 9, 2008 doi:10.1152/ajpregu.00467.2007.-Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17␤-estradiol (E2) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic E2 supplementation (80 g ⅐ kg Ϫ1 ⅐ day Ϫ1 , i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of E2 with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in E2-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that longterm supraestrus E2 levels and acute inhibition of nNOS activity had similar functional effects. Finally, E2 decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of E2 increased urethral tone through inhibition of nNOS expression, whereas physiological levels of E2 had no effect. estrogen; neurourology; urethra UP TO 50% OF WOMEN ARE REPORTED to suffer from urinary incontinence or overactive bladder (22). Lower urinary tract function is intimately interrelated to physiological estradiol (E 2 ) variations, as illustrated by the transitory increase in urethral pressure at the peak of E 2 secretion at midcycle (32), its gradual increase during pregnancy (15), and the prevalence of urinary bothers after menopause (6).In woman, estrogen therapy has been shown to prevent postmenopausal cystitis (8) and urinary atrophy and overactive bladder (6). Moreover, clinical data suggest that estrogens partly improve lower urinary tract functioning by improving local trophicity (13). However, regarding urinary incontinence, estrogens either failed to show any effect on stress urinary incontinence (24) or actually increased (in a large multicentric study) the incidence and severity of all types of urinary incontinence (12).The intricate relationship between urine storage and micturition involves a reciprocal balance in the muscle tone of bladder and urethra, which are under spinal and supraspinal controls. Autonomic regulation of the lower urinary tract physiology is driven by all three components of the autonomic nervous system. Nitric oxide (NO), the key neurotransmitter of the nonadrenergic, noncholinergic nerves ...

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Section: Discussionmentioning

confidence: 59%

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Gamé¹,

Allard²,

Escourrou³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…The decreased IRF-1 in splenocytes from estrogentreated mice, which were activated with T-cell stimulants, was surprising considering that we and others have shown that estrogen promotes IFN-g, a cytokine that induces IRF-1 (Fox et al 1991, Karpuzoglu-Sahin et al 2001, Maret et al 2003, Gourdy et al 2005, Nakaya et al 2006. The importance of IFN-g in IRF-1 induction is evidenced by the findings that IRF-1 was markedly decreased in Con-A-activated splenocytes from IFN-g K / K mice.…”

Section: Discussionmentioning

confidence: 77%

17β-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes

Lengi¹,

Phillips²,

Karpuzoglu³

et al. 2006

Journal of Molecular Endocrinology

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Interferon regulatory factor-1 (IRF-1) is an important transcription factor that mediates interferon-g (IFN-g)-induced cellsignaling events. In this study, we examined whether 17b-estradiol alters IRF-1 in splenic lymphocytes, in view of the immunomodulatory effects of this natural female sex hormone including its ability to alter IFN-g levels. We find that IRF-1 expression is markedly downregulated in splenocytes or purified T-cells from estrogen-treated mice at all time points studied when compared with their placebo counterparts. This decrease in IRF-1 in splenocytes from estrogen-treated mice is neither due to upregulation of IRF-1-interfering proteins (nucleophosmin or signal transducer and activator of transcription (STAT)-5) nor due to alternatively spliced IRF-1 mRNA. Given that IFN-g is a potent inducer of IRF-1, direct addition of recombinant IFN-g to splenocytes from either wild-type or IFN-g-knockout mice, or the addition of recombinant IFN-g to purified T-cells, was expected to stimulate IRF-1 expression. However, robust expression of IRF-1 in cells from estrogen-treated mice was not seen, unlike what was observed in cells from placebo-treated mice. Diminished IFN-g induction of IRF-1 in cells from estrogen-treated mice was noticed despite comparable phosphorylated STAT-1 activation. These studies are the first to show that estrogen regulates IFN-g-inducible IRF-1 in lymphoid cells, a finding that may have implications to IFN-g-regulated immune and vascular diseases.

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“…Estrogens are not always immunosuppressive and can exacerbate autoantibody-mediated autoimmune diseases such as lupus-like syndrome [34,35] and experimental autoimmune myasthenia gravis [17]. We and others have documented an enhancing effect of E2 on antigen-specific responses of conventional CD4 1 T cells [16] as well as NKT cells [36], characterized by enhanced production of type-1 cytokines. These pro-inflammatory effects were observed in Ovx mice supplemented with low doses of exogenous E2 and were mediated through ERa signaling in hematopoietic cells [16].…”

Section: Discussionmentioning

confidence: 99%

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

et al. 2010

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Sex hormones influence immune responses and the development of autoimmune diseases including MS and its animal model, EAE. Although it has been previously reported that ovariectomy could worsen EAE, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been addressed. In this report, we now show that endogenous estrogens limit EAE development and CNS inflammation in adult female mice through estrogen receptor a expression in the host non-hematopoietic tissues. We provide evidence that the enhancing effect of gonadectomy on EAE development was due to quantitative rather than qualitative changes in effector Th1 or Th17 cell recruitment into the CNS. Consistent with this observation, adoptive transfer of myelin oligodendrocyte glycoprotein-specific encephalitogenic CD41 T lymphocytes induced more severe EAE in ovariectomized mice as compared to normal female mice. Finally, we show that gonadectomy accelerated the early recruitment of inflammatory cells into the CNS upon adoptive transfer of encephalitogenic CD4 1 T cells. Altogether, these data show that endogenous estrogens, through estrogen receptor a, exert a protective effect on EAE by limiting the recruitment of blood-derived inflammatory cells into the CNS.Key words: EAE/MS . Estrogen . Estrogen receptor . Inflammation . Th1/Th17 cells Supporting Information available onlineIntroduction MS and its prototypic animal model, EAE, are autoimmune demyelinating diseases of the CNS. In MS and EAE, the inflammatory process is mediated by T lymphocytes reactive to CNS and brain autoantigens. It is well documented that sex hormones could influence immune responses and the development of autoimmune diseases including MS and EAE [1]. Indeed, protective effects of exogenous estrogens have been extensively reported in animal models of EAE [2][3][4]. The actions of estrogens are mediated primarily through nuclear estrogen receptor (ER) a and ERb [5]. Analysis of the effect of exogenous 17b-estradiol 3489(E2) on EAE induction in ER-mutant mice clearly showed that this protective effect of E2 was mediated through ERa but not ERb [6][7][8]. Altogether, these studies support a protective role of estrogens on EAE that could explain the protective effect of pregnancy on MS [9]. Indeed, a clinical trial in women with MS has documented a beneficial effect of exogenous estriol administration [10]. Thus, although it has been shown that exogenous estrogens down modulate EAE through ERa, it is still unclear whether physiological levels of endogenous estrogens can significantly influence CNS autoimmunity [11,12]. In female mice, sex steroid hormones, such as estrogens, are mainly produced by the ovaries, and previous studies have reported that ovariectomy could worsen EAE [2,13,14]. However, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been previously examined. For instance, it is still unknown whether these effects were due to ovarian-derived estrogens or other gonadal hormones, and whether classical ER...

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Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Cited by 136 publications

References 30 publications

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

17β-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS

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Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Cited by 136 publications

References 30 publications

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

17β-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4+ T‐cell homing into the CNS

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Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4⁺ T‐cell homing into the CNS