17β‐estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis

Abstract

Cytokines and chemokines govern leukocyte trafficking, thus regulating inflammatory responses. In this study, the anti-inflammatory effects of low dose 17 beta-estradiol were evaluated on chemokine, chemokine receptor, and cytokine expression in the spinal cords (SC) of BV8S2 transgenic female mice during acute and recovery phases of experimental autoimmune encephalomyelitis (EAE). In EAE protected mice, 17 beta-estradiol strongly inhibited mRNA expression of the chemokines RANTES, MIP-1 alpha, MIP-2, IP-10, and MCP-1, and of the chemokine receptors CCR1, CCR2 and CCR5 at both time points. Conversely, ovariectomy, which abrogated basal 17 beta-estradiol levels and increased the severity of EAE, enhanced the expression of MIP-1 alpha and MIP-2 that were over-expressed by inflammatory mononuclear cells in SC. 17 beta-estradiol inhibited expression of LT-beta, TNF-alpha, and IFN-gamma in SC, but had no effect on IL-4 or IL-10, indicating reduced inflammation but no deviation toward a Th2 response. Interestingly, elevated expression of CCR1 and CCR5 by lymph node cells was also inhibited in 17 beta-estradiol treated mice with EAE. Low doses of 17 beta-estradiol added in vitro to lymphocyte cultures had no direct effect on the activation of MBP-Ac1-11 specific T cells, and only at high doses diminished production of IFN-gamma, but not IL-12 or IL-10. These results suggest that the beneficial effects of 17 beta-estradiol are mediated in part by strong inhibition of recruited inflammatory cells, resulting in reduced production of inflammatory chemokines and cytokines in CNS, with modest effects on encephalitogenic T cells that seem to be relatively 17 beta-estradiol insensitive.

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

“…Castration of male mice worsens EAE in males (17), whereas ovariectomy does not have a major impact on this disease in female mice (18,19). Such observations suggest that it is the higher level of androgens in males that is protecting this sex from EAE development.…”

“…Castration of male mice worsens EAE (17), whereas ovariectomy does not have a major impact on disease (18,19), suggesting that the higher androgen levels in males protects this sex from developing autoimmunity. Regarding possible mediators of these androgen effects, we previously identified that that the nuclear receptor peroxisome proliferator activated receptor (PPAR)α is expressed at higher levels by male vs. female T cells and appears to control T-cell proliferation and Th1 cytokine production uniquely in male mice (20).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Physiological or pharmacological fluctuations in estrogen levels have been recognised since a long time to play a regulatory role in EAE ( [13,108,111,119,150]). Oral administration of low doses of estrogenic hormones, 17beta-estradiol and ethinyl estradiol, drastically reduce the severity of EAE and this effect was reconciled with a decrease in the production of inflammatory Th1 cytokines (such as inteferon-c (IFN-c), Tumor Necrosis Factor-a (TNF-a), Interleukin (IL)-1 and IL-6), chemokines/receptors, while increasing the expression of anti-inflammatory Th2 cytokines (including IL-4, IL-5 and Transforming Growth factor-b3 (TGF-b3)) ( [13,108,150,222]).…”

“…Oral administration of low doses of estrogenic hormones, 17beta-estradiol and ethinyl estradiol, drastically reduce the severity of EAE and this effect was reconciled with a decrease in the production of inflammatory Th1 cytokines (such as inteferon-c (IFN-c), Tumor Necrosis Factor-a (TNF-a), Interleukin (IL)-1 and IL-6), chemokines/receptors, while increasing the expression of anti-inflammatory Th2 cytokines (including IL-4, IL-5 and Transforming Growth factor-b3 (TGF-b3)) ( [13,108,150,222]). This observation together with the fact that no infiltrating lymphocytes were found in the hormone-treated animals, led to the conclusion that estrogens protects mice from EAE by inhibiting the recruitment of T cells and macrophages into the CNS.…”

Multiple sclerosis; a disease of reproductive-aged women and the dilemma involving contraceptive methods

“…In one of the most typical of these studies, experimental autoimmune encephalomyelitis was induced in mice, and estradiol and ethynil estradiol were administered to investigate the effect of estrogens on neurons (15). This and other related studies have shown that estrogens decrease the production of tumor necrosis factor-α (TNF α) and other chemokines (15,16), inhibit major histocompatibility complex-II (MHC-II) expression (17), and protect dendritic cells from inflammation (18). After the administration of estrogens in the study, the decrease in the production of TNF-α, interferon gamma (IFN-gamma), and interleukin-12 (IL-12) in dendritic cells; the decrease in antigen presentation to T cells (19); and a shift from T helper-1 (TH-1) to T helper-2 (TH-2) cells were observed (19).…”