Leukotriene C₄/D₄ induces P-selectin and sialyl Lewis^x - Dependent alterations in leukocyte kinetics in vivo

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 Lewis^x (sLe^x). LTC₄ also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLe^x. 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 sLe^x-dependent increase in leukocyte rolling flux and a P-selectin-independent but sLe^x-dependent reduction in leukocyte rolling velocity, a parameter that may play an essential role in subsequent leukocyte adhesion.