Characterization of Estrogen Receptor Mediating Neutrophil Function

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Nipapan Malisorn
Noppawan Phumala Morales
Yupin Sanvarinda
Payong Wanikiat


Estrogen and its receptors play important roles in the prevention of cardiovascular
disease in women. 17β-estradiol (E2) has a direct role in the modulation of the innate
immune function. 17β-E2 attenuates the production of pro-inflammatory cytokines including
IL-1, IL-6 and TNF-α. IL-8 production is also decreased by 17β-E2 in activated monocytes.
Estrogen also has significant effects on neutrophil functions. Estrogen effects are mediated
principally by two receptor subtypes, ERα and ERβ; both are expressed in endothelial,
vascular smooth muscle cells, and immune cells. Both estrogen receptor subtypes are also
expressed on human neutrophils, but their roles in mediating estrogen effects on neutrophil
functions are remained to be elucidated. The purpose of this study was, therefore, to
characterize the estrogen receptor subtypes that mediate estrogen effects on neutrophil
functions. Neutrophils were isolated from post-menopausal women venous blood by Dextran
and Percoll gradient centrifugation. All compounds were primarily investigated for their
cytotoxic effects on neutrophils using XTT assay. Neutrophils were pre-incubated with 17β-
E2, PPT (a selective ERα agonist), and DPN (a selective ERβ agonist), then activated by LPS
or fMLP for the study of IL-8 production or adhesion molecule expression, respectively. The
IL-8 production of leukocytes was assayed using ELISA. Neutrophil surface adhesion
molecule expression was measured using flow cytometry. Neutrophil chemotaxis and
superoxide anion generation (SAG) were also investigated. The results showed that 17β-E2
and PPT inhibited fMLP-induced CD62L-selectin shedding, while DPN did not. All drugs
did not affect fMLP-induced MAC-1 expression. Both 17β-E2 and PPT attenuated IL-8
production in a dose-dependent manner. These results suggest the role of ERα on L-selectin
shedding and IL-8 production in neutrophils. In addition, neutrophil chemotaxis-induced by
rh IL-8 was inhibited by 17β-E2 and PPT, whereas SAG was inhibited by 17β-E2, PPT, and
DPN. These results suggest that the inhibitory effect of 17β-E2 on neutrophil chemotaxis is
mediated via ERα while both ERα and ERβ play roles in SAG.


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2010 Annual Meeting Abstracts/Lectures