THE CXC-CHEMOKINE NEUTROPHIL-ACTIVATING PEPTIDE-2 INDUCES 2 DISTINCT OPTIMA OF NEUTROPHIL CHEMOTAXIS BY DIFFERENTIAL INTERACTION WITH INTERLEUKIN-8 RECEPTORS CXCR-1 AND CXCR-2

The CXC-chemokines interleukin-8 (IL-8), neutrophil-activating peptide -2 (NAP-2), and melanoma growth-stimulatory activity (MGSA) are chemoa ttractants with high selectivity for neutrophils. Although IL-8 has be en shown to act as an extremely potent mediator, reports on NAP-2 and MGSA are still contradictory. Here we show for the first time that NAP -2 and MGSA induce two distinct optima of neutrophil chemotaxis. A fir st optimum is elicited within a concentration range as low as it is ch aracteristic for IL-8. However, a second optimum appears at more than 200-fold higher stimulus concentrations, at which IL-8 is inactive. In vestigating the involvement of the two chemokine receptors CXCR-1 and CXCR-2 in NAP-2-mediated chemotaxis, we observe that the cells become desensitized to the first optimum of the chemokine after selective dow nregulation of CXCR-2, while both optima disappear upon simultaneous d ownregulation of both receptors. Blocking monoclonal antibodies (MoAbs ) specific for CXCR-2 or CXCR-1 either suppress the first optimum of N AP-2-induced chemotaxis or drastically reduce the second one, respecti vely. These results provide evidence that both receptors are involved in NAP-2-induced neutrophil chemotaxis, with CXCR-2 rendering the cell s responsive to low dosages of the chemokine, and with CXCR-1 extendin g their responsiveness to NAP-2 dosages higher by several orders of ma gnitude. (C) 1997 by The American Society of Hematology.