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1 Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California 94143-0130, California, United States
* To whom correspondence should be addressed. E-mail: janadel{at}itsa.ucsf.edu.
Airways function as an innate immune organ against airborne bacteria that are inhaled and deposited in airways. One of the mechanisms of host defense is to recruit neutrophils into airways to clear the invaders. Airway epithelial cells produce neutrophil chemoattractant interleukin (IL)-8 in response to invading bacteria. Here we show a signaling pathway on the plasma surface of human airway epithelial NCI-H292 cells that regulate IL-8 production in response to a model inflammatory stimulus phorbol 12-myristate 13-acetate (PMA) and a pathophysiologic stimulus gram-negative bacterial lipopolysaccharide (LPS). First we show that EGF receptor (EGFR) and MAP kinase ERK1/2 are involved in IL-8 expression by these stimuli. Second we show that EGFR ligand TGF-
mediates IL-8 production. Third we show that tumor necrosis factor--converting enzyme (TACE) is required for IL-8 production by cleaving EGFR proligand proTGF- into soluble TGF-, activating EGFR. Lastly we show that dual oxidase (Duox)-1, a homologue of NADPH oxidase in airways, mediates TACE activation and IL-8 expression via generation of reactive oxygen species (ROS). In summary, we describe a signaling pathway Duox1-TACE-TGF--EGFR on the surface of airway epithelial (NCI-H292) cells that mediates airway epithelial defense against bacterial infection by producing IL-8. This pathway, which also regulates mucin production in human airways, provides mechanisms for killing foreign organisms and for their clearance.
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