The prevalence of
asthma is higher in pre-pubescent and aging males, and in post-pubertal females, strongly indicating that sex
steroids (especially
estrogen) may be an important modulator in
lung disease. We recently demonstrated that airway smooth muscle (ASM) expresses both alpha and beta forms of the
estrogen receptor (ERα and ERβ) in males and females, and that these receptors regulate intracellular [Ca2+ ] and ASM contractility. Although both ERα and ERβ have multiple splice variants, it is unclear if and how the expression of these variants is modulated under conditions such as chronic
inflammation/
asthma. In order to test the hypothesis that the differential expression of ERα and ERβ variants contributes to the pathogenesis of
asthma, we profiled the expression of various ERα and ERβ genes in asthmatic and inflamed (TNFα- or IL-13-treated) ASM. Gene expression was assessed at both the
mRNA and
protein levels in asthmatic ASM cells or non-asthmatic cells treated with TNFα (20 ng/ml) or
IL-13 (50 ng/ml). We observed marked variation in the expression of ER
isoforms in response to inflammatory stimuli, and in non-asthmatic versus asthmatic ASM. Changes in
protein levels of ERα and ERβ corresponded with the observed differential
mRNA patterns. Pharmacological studies implicate cytosolic (p42/44 MAPK and PI3 K) and nuclear (NFκB, STAT6, and AP-1) signaling pathways as putative mechanisms that mediate and/or regulate effects of
inflammation on ER expression. We conclude that variations in ASM ER expression profiles occur with
inflammation and that ER variants could contribute to
estrogen signaling in airway diseases such as
asthma. J. Cell. Physiol. 232: 1754-1760, 2017. © 2016 Wiley Periodicals, Inc.