title: Characterization of E-selectin-deficient mice: demonstration of overlapping function of the endothelial selectins.
abstract: The initial rolling interaction of leukocytes with the blood vessel wall during leukocyte trafficking has been postulated to rely on members of the selectin family of adhesion molecules. Two selectins, E-selectin and P-selectin, have been identified that are expressed on activated endothelial cells. Mice deficient in E-selectin expression have been produced in order to examine the role of this selectin in leukocyte trafficking. Mice homozygous for an E-selectin null mutation were viable and exhibited no obvious developmental alterations. E-selectin-deficient mice displayed no significant change in the trafficking of neutrophils in several models of inflammation. However, blocking both endothelial selectins by treatment of the E-selectin-deficient animals with an anti-murine P-selectin antibody, 5H1, significantly inhibited neutrophil emigration in two distinct models of inflammation. While neutrophil accumulation at early times during thioglycollate-induced peritonitis was dependent on P-selectin, neutrophil accumulation at later time points was blocked by 5H1 only in E-selectin-deficient mice but not in wild-type mice. Similarly, edema as well as leukocyte accumulation in a model of delayed-type hypersensitivity in the skin was almost completely prevented by blockade of P-selectin function with 5H1 in the E-selectin-deficient mice while the same treatment had no effect in wild-type mice. These data demonstrate that the majority of neutrophil migration in both models requires an endothelial selectin but that E-selectin and P-selectin are functionally redundant. These data have important implications in the use of selectin antagonists in the treatment of inflammatory disease.
authors.affiliation: Roche Research Center, Hoffmann-La Roche, Incorporated, New Jersey 07110-1199, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Labow
authors.forename: C R
authors.initials: CR
authors.lastname: Norton
authors.forename: J M
authors.initials: JM
authors.lastname: Rumberger
authors.forename: K M
authors.initials: KM
authors.lastname: Lombard-Gillooly
authors.forename: D J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: J
authors.initials: J
authors.lastname: Hubbard
authors.forename: R
authors.initials: R
authors.lastname: Bertko
authors.forename: P A
authors.initials: PA
authors.lastname: Knaack
authors.forename: R W
authors.initials: RW
authors.lastname: Terry
authors.forename: M L
authors.initials: ML
authors.lastname: Harbison
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D019040:E-Selectin; D005260:Female; D007249:Inflammation / Q000209:etiology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology; D019007:P-Selectin; D010537:Peritoneum / Q000166:cytology; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D019010:Vascular Cell Adhesion Molecule-1