Sex Differences in Estrogen Receptor α and β Levels and Activation Status in LPS‐Stimulated Human Macrophages

Abstract

Immune function, inflammation, and atherosclerosis display sex differences and are influenced by 17β-estradiol through estrogen receptors subtypes ERα and ERβ. Male tissues express active ERs, but their possible involvement in inflammation in males has never been assessed. Macrophages express both ERα and ERβ and offer the opportunity to evaluate the role of ER levels and activation in inflammation. We assessed the ability of lipopolysaccharide (LPS) to modulate, in a sex-specific way, the expression and the activation status of ERα and ERβ in blood monocytes-derived macrophages (MDMs) from men and women. MDMs were incubated with 100 ng/ml LPS for 24 h and used to evaluate ERα, ERβ, P-ERα, p38, and P-p38 expression by Western Blotting. In basal conditions, ERα and ERβ were significantly higher in female MDMs than in male MDMs. LPS up-regulated ERα and ERα phosphorylation in both sexes, with a significantly higher effect observed in male MDMs, and down-regulated ERβ level only in female MDMs. p38 and P-p38 proteins, indicative of ERβ activity, did not show sex differences both in basal conditions and after LPS treatment. Finally, ERα/ERβ and P-ERα/ERα ratios were significantly higher in male MDMs than in female ones. Our data indicate, for the first time, that LPS affects ERα but not ERβ activation status. We identify a significant role of ERα in LPS-mediated inflammatory responses in MDMs, which represents an initial step in understanding the influence of sex in the relationship between LPS and ERα. J. Cell. Physiol. 232: 340-345, 2017. © 2016 Wiley Periodicals, Inc.

Monocytes and macrophages in abdominal aortic aneurysm

“…Epidemiological studies have highlighted the association of AAA with risk factors including age, male sex, smoking, hypertension or low HDL-cholesterol levels 1 . Interestingly, these factors may impact on monocyte/ macrophage activity and function 37,[163][164][165][166][167][168] . Additional research will be required to explore the molecular pathways that could link those risk factors with the contribution of monocytes/macrophages to AAA.…”

Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle

“…Studies about ERβ and macrophage function are limited; Kramer and colleagues [ 107 ] showed that ERβ suppresses CD16 expression with no effect on the activation of MAPKs and NF-κB, while Xing et al [ 94 ] demonstrated an opposite effect showing the ability of selective ERβ activation to inhibit expression of inflammatory mediators. A recent study in human macrophages demonstrated that LPS is able to increase ERα phosphorylation but has no effect on ERβ activation [ 108 ]. This study also showed that macrophages isolated from males are more sensitive to the LPS effects than those from females.…”

The Role of Estrogen Receptors in Cardiovascular Disease

“…This was determined by measuring the removal of 3 H-cholesterol from macrophages to the liver, and subsequently to feces. Interestingly, Campesi et al reported that the presence of lipopolysaccharides, which are known to increase the morbidity and mortality of atherosclerotic diseases, give rise to a sex-specific difference in human blood-monocytes derived macrophage ERα activation, with males showing a significantly higher level of expression than females [ 63 ].…”

“…Though the mechanisms by which ERα protects against the development of atherosclerosis are widely studied, the role of ERβ remain less thoroughly investigated and controversial [ 63 , 70 ]. Similar to ERα, ERβ is known to be expressed in both endothelial and VSMC of arteries [ 70 , 71 ].…”