title: Epidermal growth factor receptor signaling mediates vesicant-induced airway epithelial secretion of interleukin-6 and production of mucin.
abstract: The chemical warfare agent sulfur mustard (HD) and its analogue nitrogen mustard (HN2) are highly reactive vesicants that can cause airway epithelial injury. However, little is known about the mechanisms governing vesicant-related airway damage. This study assessed the role of epidermal growth factor receptor (EGFR) signaling in mediating the effects of exposure to vesicants on the secretion of cytokines and production of mucin in human airway epithelial cells. Normal human bronchial epithelial cells (NHBECs) at an air-liquid interface were challenged apically with either 200 μM HN2 or medium alone (mock treatment, MT), and cultures were evaluated for receptor fate, the secretion of IL-6, and the production of both total mucin and Mucin 5AC (MUC5AC). Exposure to HN2 induced the activation of both EGFR and (44/42)mitogen-activated protein kinase ((44/42)MAPK), as well as the ubiquitination and colocalization of EGFR within lysosomal structures. Moreover, challenge with HN2 induced the up-regulation of IL-6 and MUC5AC at the mRNA and protein levels, and stimulated the secretion of total mucin in NHBECs. HN2-related effects on the secretion of IL-6 and the production of total mucin and MUC5AC were reversed by the selective EGFR inhibitor AG1478 and by an EGFR-blocking antibody. The HN2-induced activation of (44/42)MAPK and the up-regulation of IL-6 secretion in NHBECs were also largely reversed by a transforming growth factor-α (TGF-α)-blocking antibody and by the metalloprotease inhibitor GM 6001, suggesting that the HN2-related effects on EGFR signaling were TGF-α-dependent. Collectively, these findings suggest that EGFR signaling may play a significant role in mediating vesicant-induced airway epithelial injury.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Karacsonyi
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.forename: Naga
authors.initials: N
authors.lastname: Shanmugam
authors.forename: Elliott
authors.initials: E
authors.lastname: Kagan
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009077:Mucins / Q000096:biosynthesis*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014132:Trachea / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D009077:Mucins; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases