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

Bruce Walcheck, Julius Kahn, Joseph M. Fisher, Bruce B. Wang, R. Spencer Fisk, Donald G. Payan, Carol Feehan, Raj Betageri, Krzysztof Darlak, Arno F. Spatola, Takashi Kei Kishimoto

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270 Scopus citations


The L-selectin adhesion molecule is involved in guiding leukocytes to sites of inflammation. L-selectin is cleaved by an unusual proteolytic activity at a membrane-proximal site resulting in rapid shedding from the cell surface. Although it has been demonstrated that L-selectin mediates, in part, the early event of leukocyte rolling under hydrodynamic flow, 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 stimulated neutrophils, without affecting Mac-1 mobilization or general neutrophil activation, and inhibit cleavage of L-selectin in a cell-free system. Unexpectedly, the hydroxamic acid-based inhibitors 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 physiologically important for limiting leukocyte aggregation and accumulation at sites of inflammation.

Original languageEnglish (US)
Pages (from-to)720-723
Number of pages4
Issue number6576
StatePublished - Apr 25 1996


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