title: Der p, IL-4, and TGF-beta cooperatively induce EGFR-dependent TARC expression in airway epithelium.
abstract: Thymus and Activation-Regulated Chemokine (TARC) may be critical in Th2 cell recruitment in allergic inflammation; however, the mechanisms of allergen-induced TARC release are unclear. Since airway epithelium is the first line of defense to inhaled allergens, we questioned whether house dust mite allergen (Der p) can induce TARC expression in bronchial epithelial cells, how this is regulated at the molecular level, and if micro-environmental cytokines augment this effect. We examined the effects of Der p and the cytokines IL-4 and TGF-beta on TARC expression in 16HBE cells and primary bronchial asthma epithelium. Real-time PCR and immunofluorescence demonstrated that Der p induces TARC expression in bronchial epithelium. Supernatants from Der p-stimulated 16HBE cells were able to induce TARC-dependent T cell trafficking. IL-4 and TGF-beta cooperatively enhanced Der p-induced TARC expression in 16HBE cells. Specific inhibitors, immunodetection, and gel-shifts revealed that these effects are mediated by phosphorylation of the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) signaling and subsequent nuclear factor (NF)-kappaB activation. A Disintegrin And Metalloproteinase (ADAM), a family of proteins involved in shedding of various growth factors, was shown to be responsible for EGFR activation. The increase in TARC production by direct interaction of Der p with the bronchial epithelium may be an important initial step in the generation of allergic inflammation, which is further potentiated by micro-environmental cytokines. Interference with ADAM or EGFR activity may be a novel promising target to prevent TARC release and subsequent allergic inflammation.
authors.affiliation: Department of Allergology, Pulmonology, and Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, NL-9713 GZ, Groningen, The Netherlands. h.i.heijink@int.umcg.nl
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.forename: P
authors.initials: P
authors.lastname: Marcel Kies
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Henk F
authors.initials: HF
authors.lastname: Kauffman
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D040002:Dermatophagoides pteronyssinus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008875:Middle Aged; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D039741:Antigens, Dermatophagoides; C106230:CCL17 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases