title: IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor.
abstract: Microvascular endothelial cells (HMECs) express both the CXCR1 and the CXCR2, but cell migration is almost entirely mediated by the CXCR2. Similarly, NIH 3T3 cells transfected with the CXCR2 migrated toward IL-8, whereas CXCR1-transfected cells failed to do so. This situation differs from that seen in leukocytes, where chemotaxis is primarily a function of the CXCR1. To define signal transduction pathways that explain this difference in behavior, various inhibitors were used to block cell migration. Apart from inhibitors of phosphatidylinositol 3-kinase, which blocked migration in all cases, inhibition of the epidermal growth factor (EGF) receptor blocked IL-8-mediated cell migration in HMECs and in CXCR2-transfected NIH 3T3 cells, but not in RBL2H3 cells, which do not express an EGFR. Blocking Abs against the EGFR or against heparin-binding EGF-like growth factor similarly blocked IL-8-mediated cell migration and in vitro tubulogenesis in HMECs. Furthermore, inhibition of the EGFR also attenuated focus formation in NIH 3T3 expressing the CXCR2. Immunoprecipitations of the EGFR in HMECs and in NIH 3T3 cells expressing the CXCR2 confirmed that the EGFR was phosphorylated following stimulation with IL-8. However, in contrast to previous reports, e.g., for the thrombin receptor, inhibition of matrix metalloproteases blocked IL-8-mediated cell migration only partially, whereas it was ablated by inhibition of cathepsin B. These results indicate that IL-8-induced transactivation of the EGFR is mediated by the CXCR2 and involves cathepsin B, and that this pathway is important for the migratory and tumorigenic effects of IL-8.
authors.affiliation: Department of Cancer Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121, USA. ingrid@ljimm.org
authors.forename: Ingrid U
authors.initials: IU
authors.lastname: Schraufstatter
authors.forename: Khanh
authors.initials: K
authors.lastname: Trieu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: David M
authors.initials: DM
authors.lastname: Rose
authors.forename: Robert A
authors.initials: RA
authors.lastname: Terkeltaub
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000276:immunology; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D023062:Receptors, Interleukin-8A / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D016209:Interleukin-8; D017468:Receptors, Fibroblast Growth Factor; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D066246:ErbB Receptors; D002401:Cathepsin B