Neutrophil rolling altered by inhibition of L-selectin shedding in vitro

• Published in: Nature (London) 1996-04, Vol.380 (6576), p.720-723
• Main Authors: Walcheck, Bruce, Kahn, Julius, Fisher, Joseph M, Wang, Bruce B, Fisk, R. Spencer, Payan, Donald G, Feehan, Carol, Betageri, Raj, Darlak, Krzystof, Spatola, Arno F, Kishimoto, Takashi Kei
• Format: Article
• Language: English
• Subjects: Adhesion; Biological and medical sciences; Cell Adhesion - physiology; Cell interactions, adhesion; Cell Movement - drug effects; Cell Movement - physiology; Dimethyl Sulfoxide - pharmacology; Dipeptides - pharmacology; Endopeptidases - metabolism; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; Hydroxamic Acids - pharmacology; Immunity (Disease); In Vitro Techniques; L-Selectin - drug effects; L-Selectin - physiology; letter; Molecular and cellular biology; Molecular biology; multidisciplinary; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophil Activation; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - physiology; P-Selectin - physiology; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/380720a0

THE L-selectin adhesion molecule is involved in guiding leuko-cytes to sites of inflammation 1 . L-selectin is cleaved by an unusual proteolytic activity at a membrane-proximal site resulting in rapid shedding from the cell surface 2–7 . Although it has been demonstrated that L-selectin mediates, in part, the early event of leukocyte rolling under hydrodynamic flow 8–10 , the contribution of shedding to L-selectin function has remained unknown. Here we show that hydroxamic acid-based metalloprotease inhibitors block L-selectin downregulation from the cell surface of stimu-lated neutrophils, without affecting Mac-1 mobilization or gen-eral neutrophil activation, and inhibit cleavage of L-selectin in a cell-free system. Unexpectedly, the hydroxamic acid-based inhi-bitors reduced neutrophil rolling velocity under hydrodynamic flow, resulting in increased neutrophil accumulation. These results suggest that L-selectin is cleaved in seconds—much faster than previously suspected—during the process of rolling under hydrodynamic flow, and that shedding of L-selectin may contribute significantly to the velocity of leukocyte rolling. L-selectin shedding during rolling interactions may be physio-logically important for limiting leukocyte aggregation and accumulation at sites of inflammation.