IL-13 Regulation of Mucus Production

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Asthma is a chronic debilitating condition which has been on the rise in recent decades, despite widespread use of currently available therapies. Although the etiology of asthma is unknown, we have shown that the Th2 cell-derived cytokine, IL-13, is an important mediator of asthma pathogenesis. Despite this recognition, the mechanisms by which it induces the symptoms of asthma remain elusive. In an effort to elucidate the mechanisms by which IL-13 induces the asthma phenotype, we conducted a microarray analysis of IL-13-regulated genes in the murine lung. Notably, we found that IL-13 dramatically inhibits the expression of a member of a family of Na+/K+/2CI- co-transporters known as NKCC1 (Sc112a2). NKCC1 moves Na+, K+, and Cl- ions into and out of cells in an electrically neutral manner. In other systems, NKCC1 has been shown to be important in the regulation of cell volume, proliferation and vascular smooth muscle contraction. To gain a better understanding of the physiological functions of NKCC1, we have examined responses to IL-13 in NKCC1 deficient and wildtype mice. Interestingly, genetic deficiency in NKCC1 results in marked enhancement of airway responses to IL-13 administration, particularly IL-13 driven airway hyperresponsiveness (AHR) and mucus production. Thus, we hypothesize that IL-13 induces mucus cell metaplasia and AHR, at least in part, through its regulation of NKCC1 expression in the lung. Thus the overall goal of this proposal is to determine the mechanisms by which IL-13 regulates expression of this cotransporter and to determine its role in the development of mucus metaplasia and AHR. The specific aims are: 1) To determine the mechanisms by which IL-13 regulates NKCC1 expression, we will conduct a series of studies designed to determine the effects of IL-13 on the temporal and spatial expression of NKCC1 in the airways and to define the receptor signaling pathways mediating IL-13 suppression of NKCC1 expression in vivo and in vitro; 2) To determine the mechanisms by which IL-13 suppression of NKCC1 activity leads to mucus production in vitro, we will compare the consequences of NKCC1 deficiency on mucus cell changes (i.e. goblet cell numbers, mucin gene expression, mucus accumulation, mucus secretion) in primary epithelial cells derived from NKCC1 KO and wildtype mice; 3) To determine the mechanisms by which IL-13 suppression of NKCC1 expression leads to development of AHR in vivo, we will test the hypothesis that NKCC1 gene regulation in the epithelium alone confers susceptibility to asthma. To this end, we will examine the allergic phenotype in the following murine strains epithelial-specific IL-4Ra overexpressing transgenic (Tgs); an inducible epithelial specific NKCC1 Tgs). A better understanding of the role of this family of ion cotransporters in asthma pathophysiology should guide development of novel strategies for the treatment of this debilitating disease.