Malformin-a1 inhibits the binding of interleukin-1β (il1β) and suppresses the expression of tissue factor in human endothelial cells and monocytes

Abstract

Malformin-A1, a cyclic pentapeptide of microbial origin, antagonized in a competitive manner the binding of 125I-IL1β (interleukin-1β) to human monocytes and cultured human umbilical vein endothelial cells (HUVEC) with ic 50 values (doses which reduce specific binding by 50%) of 250 ± 80 and 230 ± 25 nM, respectively (N = 3). IL1 increased in a dose-dependent manner the expression of tissue factor, a ubiquitous membrane-anchored glycoprotein that initiates blood coagulation at the surface of HUVEC and human monocytes. Malformin-A1 strongly inhibited IL1-induced tissue factor expression in HUVEC and monocytes with ic 50 values of 420 ± 35 and 105 ± 25 nM, respectively (N = 3), and reduced IL1-induced expression of intercellular adhesion molecule-1 (ICAM-1, CD54) on HUVEC ( ic 50 = 125 ± 18 nM ) (N = 4). These observations demonstrate that malformin-A1 recognizes and blocks IL1β binding to its receptor sites on monocytes and endothelial cells and protects these cells from IL1-induced procoagulant changes.