Estrogen Inhibits Systemic T Cell Expression of TNF-α and Recruitment of TNF-α+ T Cells and Macrophages into the CNS of Mice Developing Experimental Encephalomyelitis

Ito, Atsushi; Buenafe, Abigail C.; Matejuk, Agata; Zamora, Alex; Silverman, Marc; Dwyer, Jami; Vandenbark, Arthur A.; Offner, Halina

doi:10.1006/clim.2001.5175

Cited by 52 publications

(36 citation statements)

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“…27 The protective effect of E2 was associated with diminished migration of encephalitogenic T cells into the CNS and effects on dendritic cells and macrophages. 28,29 Recently, we also showed using knockout mice that Esr1 is required for the protective effect of E2 on EAE. The pathogenic role for myelinspecific T lymphocytes in EAE suggested that E2-mediated protection from EAE might be mediated through direct effects on Esr1-positive T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…E2-induced down-regulation of TNF-␣ and MIP-2 at the transcriptional level was consistently observed, suggesting a primary role for TNF-␣-producing macrophages and dendritic cells in E2 protection. 28 A sequential regulatory cascade in which TNF-␣ induces MIP-2 expression in the CNS may be primarily responsible for recruiting CCR2 ϩ MIP-2-responsive monocyte/macrophage cells to the diseased CNS in the absence of E2. E2 induced a reduction in TNF-␣, MIP-2, and CCR2 expression; prevented CNS inflammation; and protected mice from developing disease.…”

Section: Discussionmentioning

confidence: 99%

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T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

Polanczyk

Jones

Subramanian

et al. 2004

The American Journal of Pathology

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Gender influences mediated by 17␤-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-␣ (Esr1) is crucial for the protective effect of 17␤-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wildtype Esr1؉/؉ or Esr1 knockout (Esr1؊/؊) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1؉/؉ diseaseinducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

Polanczyk

Jones

Subramanian

et al. 2004

The American Journal of Pathology

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“…Two weeks before passive transfer of IL-12 and IL-18 culture-enhanced MOG 35-55 -specific T cell lines, mice were implanted with 2.5-or 15-mg E2 pellets, which maintain a constant serum E2 levels of 1,500 -2,000 and 5,000 -10,000 pg/ml, respectively. Our previous studies established that 2.5 mg and higher doses of E2 pellets were very effective in suppressing active EAE induced in C57BL/6 mice by immunization with MOG peptide in CFA (20,21). As shown in Table II, the higher 15-mg dose of E2 was very effective at inhibiting EAE induced by adoptive transfer of 4 million IL-12-and IL-18-coactivated MOG -specific T cells, as shown by the lower incidence, delayed onset, and reduced peak and CDI scores compared with vehicle-treated mice.…”

Section: Pregnancy Level Of Estrogen Can Abrogate Eae Passively Transmentioning

confidence: 99%

Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive

Ito

Matejuk

Hopke

et al. 2003

The Journal of Immunology

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The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG35–55). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients. Coculture of T cells with IL-12 enhanced the secretion of IFN-γ, but not TNF-α, whereas coculture with IL-18 enhanced the secretion of TNF-α, but not INF-γ. However, coculture with both IL-18 and IL-12 induced high levels of both TNF-α and IFN-γ. Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18. Finally, estrogen treatment, previously found to inhibit both TNF-α and IFN-γ production, completely abrogated all signs of passive EAE. These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-γ/CCR5 and TNF-α/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.

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“…Kim et al [54] have found significantly increased production of IL-10 in cultured splenocytes obtained from estriol-treated animals [54]. Decreased number of TNF-α producing T lymphocytes in CNS and spleen suspension as a consequence of 17-β-estradiol administration has been demonstrated by Ito et al [65]. Subramanian et al [62] have observed a tendency toward reduced secretion of IFN-γ, TNF-α, and IL-6 from activated T lymphocytes along with decreased incidence and severity of EAE under ethinyl-estradiol treatment.…”

Section: Influence Of Gender and Sex Hormones On Eaementioning

confidence: 86%

Sex Hormones and Multiple Sclerosis

Trenova¹

2016

Trending Topics in Multiple Sclerosis

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Experimental and clinical data about the influence of sex hormones on the course of multiple sclerosis (MS) grow rapidly during the past two decades. Estrogens, progesterone, and androgens have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in animals, and pregnancy in women is associated with a dramatic reduction in disease activity. Immunomodulatory and neuroprotective properties of sex hormones are the most probable underlying mechanisms, creating a background for testing similar hormonal treatments in humans. Several pilot studies in this field present promising results, but larger trials are necessary to identify the adverse events and to estimate precisely the place of sex steroids in multiple sclerosis therapeutic strategies.The objective of this chapter is to summarize the recent advances in the research about the effects of sex steroids in EAE and MS and to create a ground for the development of more powerful treatments in the future.

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Estrogen Inhibits Systemic T Cell Expression of TNF-α and Recruitment of TNF-α+ T Cells and Macrophages into the CNS of Mice Developing Experimental Encephalomyelitis

Cited by 52 publications

References 36 publications

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive

Sex Hormones and Multiple Sclerosis

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