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The CXC-Chemokine Neutrophil-Activating Peptide-2 Induces Two Distinct Optima of Neutrophil Chemotaxis by Differential Interaction With Interleukin-8 Receptors CXCR-1 and CXCR-2
Andreas Ludwig,
Frank Petersen,
Stefan Zahn,
Otto Götze,
Jens-Michael Schröder,
Hans-Dieter Flad, and
Ernst Brandt
From the Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel; the Department of Immunology, University of Göttingen, Göttingen; and the Department of Dermatology, University of Kiel, Kiel, Germany.
The CXC-chemokines interleukin-8 (IL-8), neutrophil-activating peptide-2 (NAP-2), and melanoma growth-stimulatory activity (MGSA) are chemoattractants with high selectivity for neutrophils. Although IL-8 has been 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 first optimum is elicited within a concentration range as low as it is characteristic for IL-8. However, a second optimum appears at more than 200-fold higher stimulus concentrations, at which IL-8 is inactive. Investigating 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 downregulation of CXCR-2, while both optima disappear upon simultaneous downregulation of both receptors. Blocking monoclonal antibodies (MoAbs) specific for CXCR-2 or CXCR-1 either suppress the first optimum of NAP-2-induced chemotaxis or drastically reduce the second one, respectively. These results provide evidence that both receptors are involved in NAP-2-induced neutrophil chemotaxis, with CXCR-2 rendering the cells responsive to low dosages of the chemokine, and with CXCR-1 extending their responsiveness to NAP-2 dosages higher by several orders of magnitude.
Blood, Vol. 90 No. 11 (December 1), 1997:
pp. 4588-4597
© 1997 by The American Society of Hematology.
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