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(Circulation. 2000;101:1867.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Endothelial Cell Activation by Pore-Forming Structures

Pivotal Role for Interleukin-1

Soheyla Saadi, PhD; Robert A. Holzknecht, BS; Christian P. Patte, BS; Jeffrey L. Platt, MD

From the Department of Surgery (S.S., R.A.H.) and Departments of Pediatrics and Immunology (C.P.P., J.L.P.), Mayo Clinic, Rochester, Minn.

Correspondence to Soheyla Saadi, PhD, Mayo Clinic, Medical Science 2–66, Rochester, MN 55905. E-mail saadi.soheyla{at}mayo.edu

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-1. 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.

Methods and Results—Exposure of ECs to complement caused upregulation of mRNAs for E-selectin, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, I-B, interleukin (IL)-1, IL-1ß, 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-1, because complement-mediated EC activation was inhibited by anti–IL-1 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-1.

Key Words: pore-forming peptides • endothelium • interleukin-1

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