IL-1 beta mediates induction of hepatic type 1 plasminogen activator inhibitor in response to local tissue injury

Type 1 plasminogen: activator inhibitor (PAI-1), a major physiological inhi bitor of plasminogen activation, is an important component of the hepatic a cute phase response. We studied the acute phase regulation of murine hepati c PAI-1 in response to systemic toxicity and local tissue injury in both wi ld-type mice and in mice in which the interleukin (IL)-1 beta gene had been inactivated by gene targeting. Endotoxin induced plasma PAI-1 antigen leve ls and PAI-1 mRNA accumulation in liver to the same extent in both wild-typ e and IL-l beta-deficient mice. In contrast, turpentine increased plasma PA I-1 and hepatic PAI-1 mRNA accumulation in wild-type mice but not in IL-l b eta-deficient mice. Intraperitoneal injection of murine IL-1 beta rapidly i ncreased plasma PAI-1 and hepatic PAI-1 mRNA:in both wild-type and IL-1 bet a-deficient mice. These results Suggest that IL-1 beta is a critical induce r of hepatic PAI-1 gene expression during the acute phase response to local tissue injury. In situ hybridization studies revealed that hepatocytes are the cells primarily responsible for the hepatic expression of the PAI-1 ge ne induced by lipopolysaccharide and turpentine.