title: Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin.
abstract: Selectins support the capture and rolling of leukocytes in venules at sites of inflammation and in lymphocyte homing. Gene-targeted mice with null mutations at the L-, E-, or P-selectin locus develop normally and show mild (E-/-) to moderate (P-/-, L-/-) defects in inflammatory cell recruitment. Mice lacking both P- and E-selectin (E/P-/-) have severe neutrophilia and spontaneous skin infections that limit their life span. Other combinations of selectin deficiency have not been investigated. We have generated novel mice lacking L- and P-selectin (L/P-/-), L- and E-selectin (L/E-/-), or all three selectins (E/L/P-/-) by bone marrow transplantation. L/P-/- mice (only E-selectin present) show an absence of leukocyte rolling after trauma and severely reduced rolling (by approximately 90%) in inflammation induced by TNF-alpha. Residual rolling in L/P-/- mice was very slow (3.6 +/- 0.2 micrometers/s after TNF-alpha). L/E-/- mice (only P-selectin present) showed rolling similar to that of L-/- at increased velocities (15.1 +/- 0.3 micrometer/s). The number of adherent leukocytes after 2 or 6 h of TNF-alpha treatment was not significantly reduced in L/E-/- or L/P-/- mice. E/L/P-/- mice showed very little rolling after TNF-alpha, all of which was blocked by mAb to alpha4 integrin. Adherent and emigrated neutrophils were significantly reduced at 6 h after TNF-alpha. We conclude that any one of the selectins can support some neutrophil recruitment but eliminating all three selectins significantly impairs neutrophil recruitment.
authors.affiliation: Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
authors.forename: U
authors.initials: U
authors.lastname: Jung
authors.forename: K
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D019041:L-Selectin / Q000235:genetics / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011828:Radiation Chimera / Q000276:immunology; D019087:Selectins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014947:Wounds and Injuries / Q000097:blood / Q000276:immunology
chemical_list: D019040:E-Selectin; D019007:P-Selectin; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin