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© The Rockefeller University Press, 0022-1007/1997/3/1077/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 6, March 17, 1997 1077-1088

Articles

The Association between {alpha}4-Integrin, P-Selectin, and E-Selectin in an Allergic Model of Inflammation

Samina Kanwar*, Daniel C. Bullard{ddagger}, Michael J. Hickey*, C. Wayne Smith§, Arthur L. Beaudet||, Barry A. Wolitzky, and Paul Kubes*

From the * Immunology Research Group, Department of Medical Physiology, University of Calgary, Calgary, Alberta T2N 4N1, Canada; {ddagger} Department of Comparative Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294; § Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030-2399; || Department of Molecular and Human Genetics, Baylor College of Medicine and Howard Hughes Medical Institute, Houston, Texas 77030; and Department of Inflammation/Autoimmune Diseases, Hoffmann La-Roche Inc., Nutley, New Jersey 07110-1199

In this study, we examined the relationship between the endothelial selectins (P-selectin and E-selectin) and whether they are critical for {alpha}4-integrin–dependent leukocyte recruitment in inflamed (late phase response), cremasteric postcapillary venules. Animals were systemically sensitized and 2 wk later challenged intrascrotally with chicken ovalbumin. Leukocyte rolling flux, adhesion, and emigration were assessed at baseline and 4 and 8 h postantigen challenge. There was a significant increase in leukocyte rolling flux, adhesion, and emigration in sensitized and challenged mice at both 4 and 8 h. At 8 h, the increase in leukocyte rolling flux was ~50% inhibitable by an anti–{alpha}4-integrin antibody, 98% inhibitable by fucoidin (a selectin-binding carbohydrate), and 100% inhibitable by an anti–P-selectin antibody. P-selectin–deficient animals displayed no leukocyte rolling or adhesion at 8 h after challenge. However, at 8 h there were many emigrated leukocytes in the perivascular space suggesting P-selectin–independent rolling at an earlier time point. Indeed, at 4 h postantigen challenge in P-selectin–deficient mice, there was increased leukocyte rolling, adhesion, and emigration. The rolling in the P-selectin– deficient mice at 4 h was largely {alpha}4-integrin dependent. However, there was an essential E-selectin– dependent component inasmuch as an anti–E-selectin antibody completely reversed the rolling, and in E-selectin and P-selectin double deficient mice rolling, adhesion and emigration were completely absent. These results illustrate that P-selectin underlies all of the antigen-induced rolling with a brief transient contribution from E-selectin in the P-selectin–deficient animals. Finally, the antigen-induced {alpha}4-integrin–mediated leukocyte recruitment is entirely dependent upon endothelial selectins.

Address correspondence to Dr. Paul Kubes, Immunology Research Group, Department of Medical Physiology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1 Canada.

1Abbreviations used in this paper: Dv, venular diameter; dyn, dynes; PCA, passive cutaneous anaphylaxis; VCAM-1, vascular cell adhesion molecule 1.


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