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Published ahead of print on September 15, 2006, doi:10.1165/rcmb.2006-0180OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 2, February 2007, 244-253

A more recent version of this article appeared on February 1, 2007
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Submitted on May 19, 2006
Revised on September 13, 2006

Interleukin-13 and EGF Receptor Have Critical but Distinct Roles in Epithelial Cell Mucin Production

Guohua Zhen1, Sung Woo Park2, Louis T Nguyenvu2, Madeleine W Rodriguez2, Rebecca Barbeau2, Agnes C Paquet2, and David J Erle2*

1 Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Internal Medicine, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, Hubei, China, 2 Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

* To whom correspondence should be addressed. E-mail: David.Erle{at}ucsf.edu.

Overproduction of mucus is a central feature of asthma. The cytokine interleukin-13 (IL-13), the epidermal growth factor receptor (EGFR), and the 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 (NHBE) 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 TGF{alpha}. However, there was constitutive release of TGF{alpha} from NHBE cells and inhibition of TGF{alpha} 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.




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