title: Functional expression of the C-X-C chemokine receptor CXCR4 by human bronchial epithelial cells: regulation by proinflammatory mediators.
abstract: CXCR4 and its ligand stromal cell-derived factor 1alpha (SDF-1alpha) have recently been implicated in the development of airway inflammation in a mouse model of allergic airway disease. Here we report, for the first time, the expression of a functional CXCR4 in primary human normal bronchial epithelial cells and the regulation of CXCR4 gene expression by proinflammatory mediators. Both bradykinin (BK) and IL-1beta induced an accumulation of CXCR4 mRNA in normal bronchial epithelial cells in a time-dependent manner, with peak levels of CXCR4 mRNA reached between 4 and 24 h after stimulation. Ligand activation of CXCR4 in airway epithelial cells resulted in the activation of the extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun amino-terminal kinase signaling pathways and calcium mobilization. Pretreatment of airway epithelial cells with BK or IL-1beta enhanced SDF-1alpha induced phospho-extracellular signal-regulated kinase and calcium mobilization, in addition to increasing the level of CXCR4 protein. Finally, we describe the expression of CXCR4 mRNA and its regulation by BK in vivo in human nasal tissue. CXCR4 mRNA levels are significantly higher in the nasal tissue of symptomatic allergic rhinitis subjects compared with normal subjects. Moreover, BK challenge significantly increased CXCR4 mRNA levels in nasal tissue of mild allergic rhinitis subjects in vivo, but not normal controls. In conclusion, this study demonstrates that human airway epithelial cells respond to proinflammatory mediators by up-regulating the chemokine receptor CXCR4, thus enabling the cells to respond more effectively to constitutively expressed SDF-1alpha. This may lead to enhanced activation of intracellular signaling pathways resulting in the release of mediators involved in inflammatory allergic airway disease.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. eddlesto@scripps.edu
authors.forename: Jane
authors.initials: J
authors.lastname: Eddleston
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Christiansen
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Zuraw
mesh_terms: D001920:Bradykinin / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009296:Nasal Cavity / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D012220:Rhinitis / Q000276:immunology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D018836:Inflammation Mediators; D007375:Interleukin-1; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D020928:Mitogen-Activated Protein Kinases; D001920:Bradykinin