Innate immune mucin production via epithelial cell surface signaling: relationship to allergic disease.
OBJECTIVE
Airway epithelial surface signaling is provided by epidermal growth factor receptor (EGFR) phosphorylation, resulting in innate immune responses. Here the focus is the EGFR cascades leading to immune mucin responses. The review is timely because recent discoveries implicate these pathways in multiple innate immune defenses in addition to mucin production.


RESULTS
EGFR activation causes mucin production and inhibition prevents mucin production by multiple stimuli. The receptors and their epithelial-bound proligands are examined. Proteases cleave and release soluble ligand, which then activates EGFR. A surface metalloprotease, tumor necrosis factor alpha-converting enzyme (TACE), modulates proligand release (and thus EGFR activation). TACE is activated by reactive oxygen species, which can be produced by a novel molecule, dual oxidase-1, which provides reactive oxygen species for TACE cleavage. Upstream of dual oxidase-1 are epithelial receptors that receive messages from inhaled irritants and stimulate the dual oxidase-1-TACE-ligand-EGFR cascade.


CONCLUSIONS
The EGFR surface signaling pathways are reviewed, with the focus on mucin production, involving human airway epithelial cultures and animal studies, including relevant studies of asthma in humans. Future studies may broaden the innate defenses and utilize these surface signaling pathways in various epithelia, with a variety of pathophysiologic stimuli, with the ultimate aim of examining these pathways in inflammatory diseases.
Nadel
Jay A
JA
Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA. J.Nadel@ucsf.edu
D000818:Animals; D002462:Cell Membrane / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D007113:Immunity, Innate; D009077:Mucins / Q000096:biosynthesis*; D015398:Signal Transduction / Q000276:immunology*
D009077:Mucins