γ-interferon modulates von Willebrand factor release by cultured human endothelial cells

Abstract

Endothelial cells (EC) synthesize and secrete von Willebrand factor (vWF), a multimeric glycoprotein required for normal hemostasis. Within human endothelial cells. vWF multimers of extremely high molecular weight are stored in rod-shaped organelles known as Weibel-Palade bodies. Inflammatory mediators, such as interleukin-1, induce in vitro a variety of procoagulant responses by EC, including the secretion of stored vWF. We postulated that other inflammatory mediators might act to balance this procoagulant reaction, thereby assisting in the maintainence of blood fluidity during immune activation. Both γ-interferon (γ-IFN) and tumor necrosis factor (TNF) were found to act independently and cooperatively to depress the stimulated release of vWF from EC. Analysis of stored vWF in either γ-IFN and/or TNF-treated EC demonstrated a loss of high molecular weight multimers while immunofluorescent studies documented a loss of visible Weibel-Palade bodies. This suggests that γ-IFN and TNF interfere with normal vWF storage. γ-IFN acted in a dose-, time-, and RNA-dependent fashion, and its inhibition of vWF release was reversible with time. No effect of γ-IFN on EC was noted when anti-serum to γ-IFN was added. Unlike γ-IFN, α-interferon did not effect EC vWF. Therefore, γ-IFN and TNF may be important in decreasing vWF release during inflammatory or immunologic episodes.