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* Division of Allergy and Clinical Immunology,
Department of Dermatology,
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224; and
AstraZeneca, R&D Charnwood, Loughborough, United Kingdom
The function of chemokine receptors on structural cells is only partially known. We previously reported the expression of a functional CCR3 receptor on airway epithelial cells (EC). We speculated that CCR3 might drive wound repair and expression of inflammatory genes in epithelium. The human airway EC lines BEAS-2B, 16-HBE, and primary bronchial EC were used to test the effect of in vitro challenge with the CCR3 ligands CCL11/eotaxin, CCL24/eotaxin-2, or CCL26/eotaxin-3 on 1) wound repair, using an established wound model; 2) cell proliferation and chemotaxis, using specific fluorometric assays; and 3) gene expression, using pathway-specific arrays for inflammatory and profibrotic cytokines, chemokines, and chemokine receptor genes. Agonist specificity was tested by cell pretreatment with an AstraZeneca CCR3 antagonist (10–8 – 10–6 M). CCL24 challenge significantly accelerated epithelial wound closure, with similar effects exerted by CCL11 and CCL26. This effect was time dependent, submaximal at 1 nM, and comparable in potency to epidermal growth factor. CCL24 induced a concentration-dependent increase in EC proliferation and chemotaxis, with significant effects observed at 10 nM. The AstraZeneca compound selectively inhibited these CCL24-mediated responses. CCL11 induced the up-regulation of several profibrogenic molecules such as fibroblast growth factor 1 and 5 and of several CC and CXC chemokines. Epithelial immunostaining for CCR3 was stronger in bronchial biopsies of asthmatics displaying marked inflammatory changes than in nondiseased samples. Epithelial CCR3 participates in key functions for wound repair, amplifies the expression of profibrogenic and chemokine transcripts, and appears up-regulated in inflamed asthmatic airways.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funding from AstraZeneca and National Institutes of Health Grants RO1 AI 44242-01A2 (to C.S.) and RO1AI 45839 (to L.B.).
2 Address correspondence and reprint requests to Dr. Cristiana Stellato, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail address: stellato{at}jhmi.edu
3 Abbreviations used in this paper: EC, epithelial cell; AZ XX, AstraZeneca CCR3 antagonist; BMP, bone morphogenic protein; EGF, epidermal growth factor; FGF, fibroblast growth factor; HVEM-L, herpes virus entry mediator-ligand; PBEC, primary bronchial EC; TNFSF, TNF (ligand) superfamily; RT, room temperature; MFI, mean fluorescence intensity.
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