Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pathology

Supervisor

Cameron, Lisa

Abstract

T helper (Th2) cells are increased in asthma and mediate allergic inflammation through production of type 2 cytokines (interleukin-4, -5 and -13). One pathway to activate Th2 cells is through chemoattractant-homologous receptor expressed on Th2 cells (CRTh2), a receptor for prostaglandin D2 (PGD2). Glucocorticoids (GCs) are the main treatment for allergic disease, due to their ability to suppress type 2 cytokine production and induce apoptosis. Incidence and severity of asthma is greater in women than men, which may be related to sex-specific efficacy of GCs. Recently, our laboratory found that severe asthmatic women had more circulating Th2 cells than men and that the proportion of Th2 cells were positively correlated with daily dose of inhaled GC in women, but not men. Since estrogen has been shown to influence type 2 cytokine production, I hypothesized this pathway interferes with the anti-inflammatory effect of GC on Th2 cells. I found that Th2 cells co-treated with an estrogen receptor alpha agonist and GC exhibited a significant increase in surface and total CRTh2 protein levels which was associated with enhanced IL-5 and IL-13 production in response to PGD2. Th2 cell apoptosis induced by GC was reduced with ER alpha agonism. These results show that GC and ER alpha signaling enhances Th2 cell responses and survival. In vivo this interaction may represent a mechanism by which Th2 cells and type 2 responses are sustained in women, influencing severity of asthma.

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