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Am J Physiol Lung Cell Mol Physiol 294: L1068-L1075, 2008. First published March 28, 2008; doi:10.1152/ajplung.00025.2008
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Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium

Jonathan L. Koff,1,2 Matt X. G. Shao,1,2 Iris F. Ueki,1 and Jay A. Nadel1,2,3

1Cardiovascular Research Institute and Departments of 2Medicine and 3Physiology, University of California-San Francisco, San Francisco, California

Submitted 14 January 2008 ; accepted in final form 26 March 2008

Toll-like receptors (TLRs) are critical for the recognition of inhaled pathogens that deposit on the airway epithelial surface. The epithelial response to pathogens includes signaling cascades that activate the EGF receptor (EGFR). We hypothesized that TLRs communicate with EGFR via epithelial signaling to produce certain innate immune responses. Airway epithelium expresses the highest levels of TLR2, TLR3, TLR5, and TLR6, and here we found that ligands for these TLRs increased IL-8 and VEGF production in normal human bronchial epithelial cells. These effects were prevented by treatment with a selective inhibitor of EGFR phosphorylation (AG-1478), a metalloprotease (MP) inhibitor, a reactive oxygen species (ROS) scavenger, and an NADPH oxidase inhibitor. In an airway epithelial cell line (NCI-H292), TNF-{alpha}-converting enzyme (TACE) small interfering RNA (siRNA) was used to confirm that TACE is the MP involved in TLR ligand-induced IL-8 and VEGF production. We show that transforming growth factor (TGF)-{alpha} is the EGFR ligand in this signaling cascade by using TGF-{alpha} neutralizing antibody and by showing that epithelial production of TGF-{alpha} occurs in response to TLR ligands. Dual oxidase 1 (Duox1) siRNA was used to confirm that Duox1 is the NADPH oxidase involved in TLR ligand-induced IL-8 and VEGF production. We conclude that multiple TLR ligands induce airway epithelial cell production of IL-8 and VEGF via a Duox1-> ROS-> TACE-> TGF-{alpha}-> EGFR phosphorylation pathway. These results show for the first time that multiple TLRs in airway epithelial cells produce innate immune responses by activating EGFR via an epithelial cell signaling cascade.

TNF-{alpha}-converting enzyme; dual oxidase; transforming growth factor-{alpha}; cell signaling


Address for reprint requests and other correspondence: J. A. Nadel, 513 Parnassus Ave., Box 0130, Univ. of California-San Francisco, San Francisco, CA 94143-0130 (e-mail: jay.nadel{at}ucsf.edu)




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