Down-regulation of murine tissue factor pathway inhibitor mRNA by endotoxin and tumor necrosis factor-alpha in vitro and in vivo

Tissue factor pathway inhibitor (TFPI) is the protease inhibitor that regul ates the extrinsic coagulation pathway initiated by the factor VIIa/TF comp lex. In this study, we first investigated tissue distribution of TFPI mRNA in the mouse and found that TFPI mRNA expression level was by far the highe st in the lung, followed by the heart, adrenal, and adipose tissue. Since l ittle has been known concerning the regulation of TFPI gene expression in v ivo, we further analyzed the changes in the TFPI mRNA level in murine tissu es after intraperitoneal injection of lipopolysaccharide (LPS), tumor necro sis factor-alpha (TNF-alpha), and interleukin-1 (IL-1). LPS and TNF-alpha d ramatically decreased TFPI mRNA expression in four tissues examined (e.g., lung, heart, kidney, and adipose tissue), whereas the suppressive effect of IL-1 on TFPI mRNA was limited. The down-regulation of TFPI mRNA expression by LPS and TNF-alpha was also observed in cultured mouse endothelial cells and in cardiomyocyte cell lines. The decreased TFPI mRNA expression by LPS and TNF-alpha in tissues and in the specific cell types may contribute to an increase in the local procoagulant potential, resulting in the thromboti c tendency under septic and/or inflammatory conditions. (C) 2000 Elsevier S cience Ltd. All rights reserved.