Characterization of a Calcium-Activated Chloride Channel as a Shared Target of Th2 Cytokine Pathways and Its Potential Involvement in Asthma

Abstract

Interleukin (IL)-9 is a T helper (Th) 2 cytokine recently implicated as an essential factor in determining susceptibility to asthma. Transgenic mice overexpressing IL-9 exhibit many features that are characteristic of human asthma. To better understand the mechanism by which IL-9 mediates the various biologic activities in asthma, we performed suppressive subtraction hybridization with whole lung from IL-9 transgenic and control mice. Here we report the identification of mCLCA3, a calcium-activated chloride channel that was specifically induced in the lung epithelium of IL-9 transgenic mice. Expression of mCLCA3 could also be induced by intratracheal administration of IL-9 or other Th2 cytokines (IL-4, IL-13), but not by interferon-gamma. Moreover, expression of mCLCA3 was induced in the lung of antigen-exposed mice, and this induction could be suppressed by neutralizing IL-9 antibody treatment, indicating IL-9 is both necessary and sufficient to induce mCLCA3 in this experimental model of asthma. Finally, we demonstrate that hCLCA1 is the human counterpart to mCLCA3 and is also induced in vitro in human primary lung cells by Th2 cytokine treatment. Together, these data strongly implicate the involvement of mCLCA3 (in mice) and hCLCA1 (in humans) in the pathogenesis of Th2 cytokine-mediated asthmatic disorders.

Proteomic approach to identify candidate effector molecules during the in vitro immune exclusion of infectiveTeladorsagia circumcinctain the abomasum of sheep

“…Recent studies have shown that all subunits of hCLCA1 and mCLCA3 are secreted soluble proteins rather than being trans-membrane proteins [7,23]. Expression of hCLCA1 or mCLCA3 was found to be up-regulated following exposure to respiratory tract irritants that are responsible for a Th2 local inflammation [26,34]. It has been shown that at transcript and protein level, expression of hCLCA1 was up-regulated by IL-13 in normal human bronchial epithelial cells in vitro [33].…”

“…It has been shown that at transcript and protein level, expression of hCLCA1 was up-regulated by IL-13 in normal human bronchial epithelial cells in vitro [33]. Whether the secretion of the ovine CLCA protein has a direct or indirect function in worm expulsion remains unknown, although hCLCA1 has been associated with an increase in mucus production following a Th2 response of the respiratory tract [34]. Furthermore, increased expression of IL-9 resulted in increased expression of hCLCA1 mRNA by epithelial cells in patients suffering from asthma [31] suggesting that hCLCA1 may be responsible at least in part for the overproduction of mucus by the asthmatic patients.…”

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

“…Consistent with this idea, niflumic acid, a broad inhibitor of anion transport, suppresses the development of asthma in mice (12). Previous reports showed that Th2-type cytokines including IL-13 induce expression of gob-5 (mCLCA3), which had been thought to be a chloride transporter, suggesting a critical role for gob-5 in mucus overproduction in bronchial asthma (13,14). However, the role of gob-5 in asthma remains somewhat elusive at the moment, because this transporter is indeed a secretory, but not transmembrane, protein (15).…”

Association of the hCLCA1 gene with childhood and adult asthma

“…8,9 Recently, a mouse model of asthma provided the evidence that the gob-5 gene is involved in the pathogenesis of asthma. 10,11 Nakanishi et al reported that intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction, and that an adenovirusmediated overexpression of gob-5 in airway epithelia exacerbated the asthma phenotype. Zhou et al 11 showed that gob-5 is highly expressed in the lung epithelium of IL-9 transgenic mice, which exhibit many signs and symptoms characteristic of human asthma.…”

“…10,11 Nakanishi et al reported that intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction, and that an adenovirusmediated overexpression of gob-5 in airway epithelia exacerbated the asthma phenotype. Zhou et al 11 showed that gob-5 is highly expressed in the lung epithelium of IL-9 transgenic mice, which exhibit many signs and symptoms characteristic of human asthma. Asthmatic patients showed upregulation of hCLCA1 (human calcium-dependent chloride channel-1) mRNA in mucusproducing epithelium responsive to the interleukin IL-9.…”