High concentrations of ELR-containing chemokines (IL-8, gro-a) in patient samples have been associated with poor outcome of both inflammatory diseases and cancers. In animal models blockade of IL-8 was protective in acute inflammation and inhibited angiogenesis and the growth and metastasis of certain tumors. Cell migration is the theme that is common to all the IL-8 receptor mediated events, which result in such varied in vivo responses. Neutrophil chemotaxis in acute inflammation is mostly mediated by the IL-8 receptor type I (CXCR1), but the physiological role of the CXCR2 and the role of IL-8 receptors on adherent cells remain poorly defined. Both the CXCR1 and the CXCR2 are expressed on various cancer cells and as shown here on endothelial cells, where their function is far from clear. The migratory and growth promoting role of IL-8 receptors on endothelial and on cancer cells will be assessed in this grant both in vitro and in vivo with emphasis on the in vivo situation. In vitro the signal transduction cascade that leads from receptor stimulation to cytoskeletal responses will be addressed, since cytoskeletal changes are the prerequisite for the migratory responses induced by IL-8. Following this the role of the CXCR1 and CXCR2 on microvascular endothelial cells will be assessed in cell migration assays and in neutrophil/endothelial cell interaction experiments. Finally, following up on our recent observation that the CXCR2 expressed in NIH 3T3 cells causes tumors in nude mice the role of the CXCR2 in tumorigenesis and metastasis will be examined and sought to be prevented with antibody inhibition.
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