Gamma-interferon modulates von Willebrand factor release by cultured human endothelial cells.
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 maintenance of blood fluidity during immune activation. Both gamma-interferon (gamma-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 gamma-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 gamma-IFN and TNF interfere with normal vWF storage. gamma-IFN acted in a dose-, time-, and RNA-dependent fashion, and its inhibition of vWF release was reversible with time. No effect of gamma-IFN on EC was noted when anti-serum to gamma-IFN was added. Unlike gamma-IFN, alpha-interferon did not effect EC vWF. Therefore, gamma-IFN and TNF may be important in decreasing vWF release during inflammatory or immunologic episodes.
Tannenbaum
S H
SH
Clinical Pathology Department, National Institutes of Health, Bethesda, MD 20892.
Gralnick
H R
HR
D000906:Antibodies / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D015388:Organelles / Q000276:immunology / Q000648:ultrastructure; D010703:Phorbol Esters / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism*
D000906:Antibodies; D007375:Interleukin-1; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D003609:Dactinomycin; D007371:Interferon-gamma; D013917:Thrombin