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.
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.
Ludwig
A
A
Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel, Germany.
Petersen
F
F
Zahn
S
S
Götze
O
O
Schröder
J M
JM
Flad
H D
HD
Brandt
E
E
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D054360:Chemokine CXCL1; D018925:Chemokines / Q000494:pharmacology*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009504:Neutrophils / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000032:analysis; D018123:Receptors, Interleukin / Q000032:analysis / Q000378:metabolism*; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins / Q000378:metabolism; D001620:beta-Thromboglobulin
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D009363:Neoplasm Proteins; C061615:PPBP protein, human; D010455:Peptides; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D001620:beta-Thromboglobulin; C009862:connective tissue-activating peptide