TNFα and IFNγ act synergistically to induce leukocyte rolling and adhesion but not extravasation in vivo

Using intravital microscopy, we have previously shown that PAF antagonists and an anti-PECAM-1 (CD31) antibody can selectively suppress leukocyte extravasation without affecting leukocyte rolling or adhesion in IL-1β-treated mesenteric venules (Nourshargh et al., Blood 85:2553, 1995; Wakelin et al., J. Exp. Med., 184:229, 1996). In the present study, using the same model and the cytokines TNFα and IFNγ, we further demonstrate that leukocyte extravasation can he dissociated from the responses of rolling and firm adhesion, 1.p. injection of TNFα (50ng) or IFNγ (1000U) had no significant effect on the number of rolling, adherent or extravasated leukocytes as compared to saline-treated control animals after four hours. Combined injection of TNFα and IFNγ, caused a marked and significant increase in leukocyte rolling (48.9±4.2 vs. 22.0±2.5 control, p<0.01) and leukocyte adhesion (9.2±1.0 vs. 2.4±0.4 control, p<0.01). In contrast however, TNFα and IFNγ did not induce a significant increase in the number of extravasated leukocytes (2.75±0.4 vs. 1.5±0.2 control). These results show that the mechanisms involved in inducing the adhesion of leukocytes to the vascular endothelium do not necessarily trigger leukocyte extravasation in vivo, this response being regulated by distinct molecular events.