Figure 9. Scheme showing the proposed mechanism underlying the inhibitory effect of the synthetic cannabinoid WIN 55,212-2 on endothelial expression of tissue factor (TF).

The proinflammatory cytokine interleukin (IL)-1β induces TF expression in endothelial cells by separate pathways involving ceramide formation or activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinases (JNK). WIN 55,212-2 inhibits IL-1β-induced TF expression via a receptor-independent pathway resulting in a suppression of neutral sphingomyelinase (nSMase)-dependent ceramide formation as well as an interference with the activation of p38 MAPK and JNK.