Endothelial cell activation by pore-forming structures: pivotal role for interleukin-1alpha.
BACKGROUND
Interaction of complement with endothelial cells (ECs) underlies the development of inflammation and coagulation in disease. Assembly of the membrane attack complex (MAC) of complement on EC membrane, like stimulation with cytokines, upregulates tissue factor and cyclooxygenase-2 but does so via the intermediary action of IL-1alpha. We asked whether the MAC activates porcine aortic and microvascular ECs in a global manner by this mechanism and whether this mechanism is used by membrane pore-forming structures.


RESULTS
Exposure of ECs to complement caused upregulation of mRNAs for E-selectin, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, Ikappa-Balpha, interleukin (IL)-1alpha, IL-1beta, IL-8, and plasminogen activator inhibitor-1 over a period of 6 hours. The expression of these genes was not a primary response to stimulation, however, because IL-1 receptor antagonist inhibited expression of these genes. Activation of ECs by complement depended on the autocrine action of IL-1alpha, because complement-mediated EC activation was inhibited by anti-IL-1alpha antibodies. 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-1alpha.
Saadi
S
S
Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA. saadi.soheyla@mayo.edu
Holzknecht
R A
RA
Patte
C P
CP
Platt
J L
JL
D000818:Animals; D003167:Complement Activation / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation
D015938:Complement Membrane Attack Complex; D019040:E-Selectin; D007375:Interleukin-1; D008565:Membrane Proteins; D012333:RNA, Messenger