Estrogen Stimulates Th2 Cytokine Production and Regulates the Compartmentalisation of Eosinophils during Allergen Challenge in a Mouse Model of Asthma

Abstract

Background: The observation that asthma becomes more prevalent following puberty in females suggests estrogen potentiates the development of this disease. However, most studies examining the role of estrogen in rodent models of asthma are complicated by their reliance on ovariectomised mice in which hormones other than estrogen are also attenuated. Methods: We aimed to understand the influence of estrogen on allergic airway disease by using type I (tamoxifen) or type II (ICI 182,780) antagonists in female mice or delivering estradiol to male mice during aeroallergen challenge. Results: The antagonists showed that estrogen promoted both the mobilisation of bone marrow eosinophils and egression of eosinophils to the airway lumen. These findings were corroborated in male mice treated with estradiol, which increased eosinophil numbers in both blood and airways. Estrogen stimulated goblet cell hyperplasia and baseline lung resistance, but had little effect on the number of eosinophils in the bronchial submucosa or methacholine-induced airway hyperreactivity. Estrogen receptor α was expressed by CD4+ T cells from allergic mice, and estrogen promoted the production of IL-5 and IL-13, and suppressed the production of the eicosanoid 12-HETE by mediastinal lymph node cells. Conclusions: These data show that during aeroallergen challenge, estrogen stimulates Th2 cytokine production, which may be linked to its ability to suppress 12-HETE. Lung resistance at baseline, goblet cell hyperplasia and the compartmentalisation of eosinophils was also influenced by estrogen. However, estrogen does not play a major role in stimulating enhanced sensitivity to methacholine-induced lung resistance.

Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model

“…Consistent with other reports that describe effects of estrogen receptor activation on allergic inflammation (32)(33)(34), tamoxifen treatment alone appeared to have a mild antiinflammatory effect on BAL cell counts in the present study. However, tamoxifen had no effect on peribronchiolar cell numbers, airway mucin density, or AHR.…”

Importance of concomitant local and systemic eosinophilia in uncontrolled asthma

“…Few studies have evaluated the relationship between eosinophils and sex hormones. It seems that b-oestradiol significantly enhances eosinophil adhesion to human mucosal microvascular endothelial cells and their degranulation [42,43].…”

Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation

“…Estrogen is an immune modulator and is known to stimulate the production of Th2 cytokines, which include IL-4, IL-5, and IL-13 [11,13]. Our findings show that OCP use modifies the DNA-M of GATA3 gene.…”

“…The immunological effects of estrogen include increased production of TNF-α by the lungs, increased production of IL-4 by the bone marrow, and thus migration of eosinophils during allergic inflammation [11]. Furthermore, estrogen decreased expression of T-regulatory cells [12], increased expression of IL-5 and IL-13 [13], increased the differentiation of naive CD4 + cells into Th2 cells [13], and also increased Th2 responses by augmenting the production of dendritic cells [14]. Hence, estrogen and progesterone may be linked to potential immunological effects and variation in airway responses.…”