© 1995 American Heart Association, Inc.
Articles |
Leukotriene C4/D4 Induces P-Selectin and Sialyl Lewisx–Dependent Alterations in Leukocyte Kinetics In Vivo
From the Immunology Research Group, University of Calgary (Canada).
Correspondence to Dr Paul Kubes, Department of Medical Physiology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Abstract The objective of this study was to assess the effect of leukotriene C4 (LTC4) on the flux of rolling leukocytes, leukocyte rolling velocity, and leukocyte adhesion in postcapillary venules in vivo and to study the underlying molecular mechanisms involved. LTC4 (20 nmol/L) induced a rapid and significant increase in leukocyte rolling flux that was inhibitable by an anti–P-selectin antibody and soluble sialyl Lewisx (sLex). LTC4 also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLex. This LTC4-induced reduction in leukocyte rolling velocity was independent of any hemodynamic alterations. Another P-selectin effector, histamine, did not affect leukocyte rolling velocity even at >5000 times the concentration of LTC4. Treatment with an anti–L-selectin antibody had no effect on the LTC4-induced increase in leukocyte rolling or reduction in rolling velocity. Inhibition of LTC4 bioconversion to LTD4 by pretreatment with L-serine (100 µmol/L) prevented the LTC4-induced increase in leukocyte rolling flux and the LTC4-induced reduction in leukocyte rolling velocity. A subtle, yet significant, increase in leukocyte adhesion was also observed with LTC4. Pretreatment with a platelet-activating factor receptor antagonist returned the LTC4-induced leukocyte rolling velocity to baseline levels. The addition of a very low concentration of platelet-activating factor (1 nmol/L) induced significant leukocyte adhesion in the presence of LTC4 but not histamine. This study demonstrates that LTC4, via bioconversion to leukotriene D4, induces a P-selectin–dependent and sLex-dependent increase in leukocyte rolling flux and a P-selectin–independent but sLex-dependent reduction in leukocyte rolling velocity, a parameter that may play an essential role in subsequent leukocyte adhesion.
Key Words: leukotriene C4 • leukocyte rolling • sialyl Lewisx • P-selectin
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