Dominant role of L- and P-selectin in mediating CXC chemokine-induced neutrophil migration in vivo.
The role of selectins in neutrophil emigration in response to the CXC chemokines KC and MIP-2 was investigated in wild type and P-selectin deficient mice. Intrapleural injection of KC or MIP-2 induced a rapid and specific neutrophil accumulation. Emigration 2 h after KC or MIP-2 was reduced 83 - 88% by anti-L-selectin mAb and 53 - 63% by anti-P-selectin mAb. Co-administration of anti-L- and P-selectin mAbs abolished neutrophil migration induced by either chemokine. An anti-E-selectin mAb tested alone did not affect KC-induced neutrophil migration after 2 or 4 h. Moreover, anti-E-selectin did not have an additive inhibitory effect on KC-induced neutrophil migration compared with P-selectin blockade alone. This was found when neutrophil migration was measured at 2 and 4 h after KC. Despite a blood neutrophilia, neutrophil migration at 2 and 4 h after KC was markedly smaller (by approximately 90%) in P-selectin deficient mice compared with wild type animals. Responses at both time points were not decreased further in animals given E-selectin mAb but were reduced to the PBS control level in the presence of anti-L-selectin. In vitro study of cultured murine endothelial cells demonstrated that KC can directly increase cell surface P-selectin expression. These data suggest that CXC chemokine-induced neutrophil accumulation is dependent on both neutrophil L-selectin and a rapid upregulation of endothelial P-selectin but there is no evidence for E-selectin induction.
Miotla
J M
JM
Endothelial Cell Biology Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX.
Ridger
V C
VC
Hellewell
P G
PG
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D019041:L-Selectin / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D019007:P-Selectin / Q000378:metabolism / Q000502:physiology*; D010994:Pleura / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D019040:E-Selectin; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019007:P-Selectin; D019041:L-Selectin