17β-Estradiol modulates the macrophage migration inhibitory factor secretory pathway by regulating ABCA1 expression in human first-trimester placenta

Abstract

Successful pregnancy involves a series of events, most of them mediated by hormones and cytokines. Estrogens, besides being important for placental growth and embryo development, have a marked effect on the immune system exerting either pro- or anti-inflammatory properties. Numerous studies suggest that estrogens directly affect cellular function, including cytokine production. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in pregnancy, particularly during the earlier stages of placentation. Since reports on mice have shown that estrogens modulate MIF, herein we investigated the effect of estrogens on human placental MIF. By using an in vitro model of first-trimester chorionic villous explants, we found that 17beta-estradiol (E(2)) was able to modulate the release of MIF in a dose-dependent manner (10(-12) vs. 10(-9) M, P < 0.05; 10(-9) vs. 10(-5) M, P < 0.05; 10(-12) vs. 10(-5) M, P < 0.001). Unlike MIF release, no significant change in tissue MIF protein or MIF mRNA was observed. We showed evidence that E(2) concentrations (10(-9) and 10(-5) M) act on placental tissue downregulating the mRNA and protein expression of the ATP-binding cassette transporter protein A1, a membrane transporter involved in MIF secretion. These findings emphasize the mutual cooperation between hormones and cytokines and suggest that increasing estrogen levels with advancing gestation may have a major role in regulating placental MIF secretion.

The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study

“…The BMI-R230C interactions observed only in pre-menopausal women suggest that these effects may be estrogen-related. Several lines of evidence are consistent with this finding: ABCA1 -diet interactions affecting HDL-C levels have been reported in pre-menopausal women [17], improved lipid profiles have been observed in response to estrogen [42]–[43], and estrogen increased ABCA1 expression in different tissues in both mice and humans [44]–[46]. The increased risk of these metabolic parameters in pre-menopausal women is again in discrepancy with their risk of CAD, and whether this has to do with other systemic effects of estrogen, and/or with pleiotropic effects of the R230C variant in platelets, endothelium, inflammatory or other cell types remains to be elucidated.…”

Carbohydrate Intake Modulates the Effect of the ABCA1 -R230C Variant on HDL Cholesterol Concentrations in Premenopausal Women

“…Although the cause of sex-related differences is not fully understood, estrogen is known to have an effect in premenopausal women by increasing HDL-C concentrations (37,38). Moreover, there is evidence that estrogen increases ABCA1 expression in different tissues (39,40) and estrogen therapy increases ABCA1 expression in leukocytes and improves lipid profile in menopausal women (41), suggesting that the sexspecific interaction here could be mediated by the effect of estrogen on ABCA1 expression. On the other hand, although testosterone is known to be responsible for lowering HDL-C levels in men (42), this hormone has been found not to affect apoA-I or ABCA1 expression in hepatocytes or human monocyte-derived macrophages (43), which is consistent with the lack of ABCA1-nutrient interaction observed in males.…”

Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study

“…In previous studies on human placenta, Ietta et al (2010) demonstrated that low doses of E 2 stimulated MIF secretion, whereas higher doses downregulated it. Because BPA has weak estrogenic activity (Kuiper et al 1998, Rubin 2011, its stimulatory effect in MIF secretion observed here could be similar to that exerted by low doses of E 2 .…”