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J. Exp. Med.,
Volume 189, Number 6, March 15, 1999 939-948
By
From the Department of Biomedical Engineering, University of Virginia, Charlottesville,
Virginia 22908
The velocity of rolling leukocytes is thought to be determined by the expression of adhesion
molecules and the prevailing wall shear stress. Here, we investigate whether rapid cleavage of
L-selectin may be an additional physiologic regulatory parameter of leukocyte rolling. A
unique protease in the membrane of leukocytes cleaves L-selectin after activation, resulting in
L-selectin shedding. The hydroxamic acid-based metalloprotease inhibitor KD-IX-73-4 completely prevented L-selectin shedding in vitro and significantly decreased the rolling velocity of
leukocytes in untreated wild-type C57BL/6 mice from 55 to 35 µm/s in vivo. When E-selectin
was expressed on the endothelium (tumor necrosis factor [TNF]-
treatment 2.5-3 h before
the experiment), rolling velocity was 4 µm/s and did not change after the application of KD-IX-73-4. However, KD-IX-73-4 decreased mean rolling velocity by 29% from 23 to 16 µm/s in
E-selectin-deficient mice treated with TNF-. The reduction of velocity caused by KD-IX-73-4 was immediate (<5 s) after injection of KD-IX-73-4 as shown by a novel method using a
local catheter. These results establish a role for L-selectin shedding in regulating leukocyte rolling velocity in vivo.
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