Gob-5 Is Not Essential for Mucus Overproduction in Preclinical Murine Models of Allergic Asthma

Abstract

Overexpression of Gob-5 has previously been linked to goblet cell metaplasia and mucin overproduction in both in vitro and in vivo model systems. In this study, Gob-5 knockout mice were generated and their phenotype was evaluated in two established preclinical models of allergic asthma. We sought to determine whether the Gob-5-null animals could produce less mucus in response to allergic challenge, and whether this would have any impact on reducing goblet cell metaplasia and airway inflammation. We found that in the absence of a proinflammatory stimulus we could not detect an overt phenotypic difference between age and sex-matched knockout and wild-type animals. Allergic challenge with ovalbumin or intranasal administration of interleukin-13 produced a robust allergic response that was similar regardless of genotype. In addition, siRNA-mediated knockdown of CLCA-1 in cultured lung epithelial cells failed to reduce mucin expression in vitro. Thus, in contrast to previously published reports, our findings show that Gob-5 expression is not essential for mucin overproduction in vitro or in murine models of allergic asthma. Furthermore, we have also exploited the use of gene expression array analysis to investigate the possibility that a compensatory mechanism, involving other genes, may act to override the requirement for Gob-5-mediated mucus overproduction.

Murine mCLCA6 Is an Integral Apical Membrane Protein of Non-goblet Cell Enterocytes and Co-localizes With the Cystic Fibrosis Transmembrane Conductance Regulator

“…This is at variance with the mCLCA3 protein, which is entirely secreted by intestinal goblet cells (Leverkoehne and Gruber 2002;Gibson et al 2005;Mundhenk et al 2006). This difference and the different cellular locations of mCLCA3 and mCLCA6 argue against a compensatory role of mCLCA6 in the mCLCA3 knockout mouse, which has no apparent spontaneous pathology (Robichaud et al 2005). It remains unknown whether release of the larger Nterminal subunit of mCLCA6 from the membrane as shown here by acid treatment plays any significant role in vivo.…”

IL-4 Receptor Signaling in Clara Cells Is Required for Allergen-Induced Mucus Production

“…We previously showed that expression of Clca3 (also known as Gob-5) was dramatically increased by IL-13-induced activation of STAT6 in Clara cells (20). It has been reported that Clca3 plays a critical role in mucus production and mucin gene expression in vivo and in vitro (26), although a recent report demonstrates that allergen-and IL-13-induced mucus production and mucin gene induction are unimpaired in Clca3-deficient mice (50). In this study, we report that Clca3 induction was reduced by 71% in mice with Clara cellspecific disruption of Il4ra, indicating that Clca3 induction by allergen is largely dependent on direct effects of IL-4 and/or IL-13 on these cells.…”

Relationship between Calcium-Activated Chloride Channel 1 and MUC5AC in Goblet Cell Hyperplasia Induced by Interleukin-13 in Human Bronchial Epithelial Cells

“…MUC5AC proteins were localized at mucus granules, and hCLCA1 proteins were localized at the circumference of the MUC5AC proteins and goblet cell surface. Although hCLCA1 is overexpressed in the airway epithelium of asthma patients [16], Robichaud et al [33] reported that hCLCA1 is not primarily essential for mucus overproduction. Therefore, mechanisms unrelated to hCLCA1 might also be associated with GCH induced by IL-13.…”