Endothelial cell activation by pore-forming structures - Pivotal role for interleukin-1 alpha

Background-Interaction of complement with endothelial cells (ECs) underlies the development of inflammation and coagulation in disease. Assembly of th e membrane attack complex (MAC) of complement on EC membrane, like stimulat ion with cytokines, upregulates tissue factor and cyclooxygenase-2 but does so via the intermediary action of IL-1 alpha. We asked whether the MAC act ivates porcine aortic and microvascular ECs in a global manner by this mech anism and whether this mechanism is used by membrane pore-forming structure s. Methods and Results-Exposure of ECs to complement caused upregulation of mR NAs for E-selectin, intracellular adhesion molecule-1, vascular cell adhesi on molecule-1, I kappa-B alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-8, and plasminogen activator inhibitor-1 over a period of 6 hours. The express ion of these genes was not a primary response to stimulation, however, beca use IL-1 receptor antagonist inhibited expression of these genes. Activatio n of ECs by complement depended on the autocrine action of IL-1 alpha, beca use complement-mediated EC activation was inhibited by anti-IL-1 alpha anti bodies. Melittin and mastoparan, amphiphilic pore-forming peptides like the MAC, induced E-selectin through intermediary action of IL-1. Conclusions-These findings suggest that transmembrane pore-forming proteins , as a class of molecules, activate ECs through the autocrine effects of IL -1 alpha.