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IL-13 and Epidermal Growth Factor Receptor Have Critical but Distinct Roles in Epithelial Cell Mucin Production

Lung Biology Center, Department of Medicine, University of California, San Francisco; and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Correspondence and requests for reprints should be addressed to David J. Erle, UCSF, Box 2922, San Francisco, CA 94143-2922. E-Mail: david.erle{at}ucsf.edu

Overproduction of mucus is a central feature of asthma. The cytokine, IL-13, epidermal growth factor receptor (EGFR), and transcription factor, FOXA2, have each been implicated in mucus production, but the mechanistic relationships between these molecules are not yet well understood. To address this, we established a primary normal human bronchial epithelial cell culture system with IL-13–induced mucus production and gene transcript expression changes similar to those seen in vivo in mice. IL-13 did not stimulate release of the EGFR ligand, transforming growth factor (TGF)-. However, there was constitutive release of TGF- from normal human bronchial epithelial cells, and inhibition of TGF- or EGFR reduced both constitutive and IL-13–induced mucin production. Microarray analysis revealed that IL-13 and the EGFR pathway appear to have almost completely independent effects on transcript expression. IL-13 induced a relatively small set of transcripts, including several novel transcripts that might play a role in pathogenesis of allergic airway disease. In contrast, EGFR activity had extensive effects, including altered expression of many transcripts associated with cell metabolism, survival, transcription, and differentiation. One of the few common effects of IL-13 and EGFR signaling was decreased expression of FOXA2, which is known to prevent mucus production. We conclude that the IL-13 and EGFR pathways make critical but quite distinct contributions to gene regulation in airway epithelial cells, and that both pathways affect expression of the key transcription factor, FOXA2, a known regulator of mucus production.

Key Words: airway epithelium • IL-13 • epidermal growth factor receptor • FOXA2 • mucus

CLINICAL RELEVANCE Mucus production is a central feature of asthma. We show the relationship between two key pathways (IL-13 and epidermal growth factor receptor) that contribute to mucus production. We also identify a connection between these pathways and FOXA2, a key transcription factor.

 

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