title: Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells.
abstract: In sensitized individuals, exposure to allergens such as Dermatophagoides pteronyssinus (Der p) causes Th2 polarization and release of cytokines, including IL-4 and IL-13. Because Der p extracts also have direct effects on epithelial cells, we hypothesized that allergen augments the effects of Th2 cytokines by promoting mediator release from the bronchial epithelium in allergic asthma. To test our hypothesis, primary bronchial epithelial cultures were grown from bronchial brushings of normal and atopic asthmatic subjects. RT-PCR showed that each culture expressed IL-4R(alpha), common gamma-chain, and IL-13R(alpha)(1), as well as IL-13R(alpha)(2), which negatively regulates IL-13 signaling; FACS analysis confirmed IL-13R(alpha)(2) protein expression. Exposure of epithelial cultures to either Der p extracts, TNF-alpha, IL-4, or IL-13 enhanced GM-CSF and IL-8 release, and this was partially suppressible by corticosteroids. Simultaneous exposure of the epithelial cultures to IL-4 or IL-13 together with Der p resulted in a further increase in cytokine release, which was at least additive. Release of TGF-alpha was also increased by TNF-alpha and combinations of IL-4, IL-13, and Der p; however, this stimulation was only significant in the asthma-derived cultures. These data suggest that, in an allergic environment, Th2 cytokines and allergen have the potential to sustain airway inflammation through a cooperative effect on cytokine release by the bronchial epithelium. Our novel finding that IL-4, IL-13, and allergen enhance release of TGF-alpha, a ligand for the epidermal growth factor receptor that stimulates fibroblast proliferation and goblet cell differentiation, provides a potential link between allergen exposure, Th2 cytokines, and airway remodelling in asthma.
authors.affiliation: School of Medicine, Respiratory Cell and Molecular Biology Division, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: James L
authors.initials: JL
authors.lastname: Lordan
authors.forename: Fabio
authors.initials: F
authors.lastname: Bucchieri
authors.forename: Audrey
authors.initials: A
authors.lastname: Richter
authors.forename: Athanassias
authors.initials: A
authors.lastname: Konstantinidis
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.forename: Matthew
authors.initials: M
authors.lastname: Thornber
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Puddicombe
authors.forename: Diana
authors.initials: D
authors.lastname: Buchanan
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Ratko
authors.initials: R
authors.lastname: Djukanović
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D000328:Adult; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D039741:Antigens, Dermatophagoides; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008925:Mites / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000502:physiology; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D016207:Cytokines; D004338:Drug Combinations; D006023:Glycoproteins; C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D016209:Interleukin-8; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor