GCP-2-induced internalization of IL-8 receptors: hierarchical relationships between GCP-2 and other ELR+-CXC chemokines and mechanisms regulating CXCR2 internalization and recycling

The chemotactic potencies of ELR+-CXC chemokines during acute inflammation are regulated by their binding affinities and by their ability to activate, desensitize, and internalize their specific receptors, CXCR1 and CXCR2, To gain insight into the fine mechanisms that control acute inflammatory proc esses, we have focused in this study on the highly potent ELR+-CXC chemokin e Granulocyte Chemotactic Protein 2 (GCP-2), and on its ability to control the cell surface expression of CXCR1 and CXCR2, Although GCP-2 has been con sidered an effective ligand for both CXCR1 and CXCR2, our findings demonstr ated that it was a potent inducer of CXCR2 internalization only. A function al hierarchy was shown to exist between GCP-2 and 2 other ELR+-CXC chemokin es, IL-8 and NAP-2, in their abilities to induce CXCR1 and CXCR2 internaliz ation, according to the following: IL-8 > GCP-2 > NAP-2, By the use of pert ussis toxin (PTx), it was demonstrated that the actual events of G(alpha i) -coupling to CXCR2 do not have a major role in the regulation of its intern alization. Rather, CXCR2 internalization was shown to be negatively control led by induction of signaling events, as indicated by the promotion of CXCR 2 internalization following exposure to wortmannin, a potent inhibitor of p hosphatidylinositol (PI) 3 kinases and P14 kinases, Furthermore, our result s suggest that rab11(+)-endosomes participate in the trafficking of CXCR2 t hrough the endocytic pathway, to eventually allow its recycling back to the plasma membrane. To conclude, our findings shed light on the interrelation ships between GCP-2 and other ELR+-CXC chemokines, and determine the mechan isms involved in the regulation of GCP-2-induced internalization and recycl ing of CXCR2. (C) 2000 by The American Society of Hematology.