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Published ahead of print on October 5, 2006, doi:10.1165/rcmb.2006-0160OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 3, March 2007, 351-359

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Submitted on May 2, 2006
Revised on September 29, 2006

Der p, IL-4 and TGF-{beta} Cooperatively Induce EGFR-dependent TARC Expression in Airway Epithelium

Irene H Heijink1*, P. Marcel Kies1, Antoon J.M. van Oosterhout2, Dirkje S Postma3, Henk F Kauffman4, and Edo Vellenga5

1 Department of Allergology, University Medical Center Groningen, Groningen, The Netherlands; Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands, 2 Department of Allergology, University Medical Center Groningen, Groningen, The Netherlands; Department of Pulmonology, University Medical Center Groningen, Groningen, The Netherlands, 3 Department of Pulmonology, University Medical Center Groningen, Groningen, The Netherlands, 4 Department of Allergology, University Medical Center Groningen, Groningen, The Netherlands, 5 Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands

* To whom correspondence should be addressed. E-mail: H.I.Heijink{at}int.umcg.nl.

Rationale: 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. Objectives: 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. Methods: We examined the effects of Der p and the cytokines IL-4 and transforming growth factor (TGF)-{beta} on TARC expression in 16HBE cells and primary bronchial asthma epithelium. Measurements and main results: 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 (EGF) receptor, mitogen-activated protein kinase (MAPK) signaling and subsequent nuclear factor (NF)-{kappa}B activation. A Disintegrin And Metalloproteinase (ADAM), a family of proteins involved in shedding of various growth factors, was shown to be responsible for EGF receptor activation. Conclusions: 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.




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