ENDOTOXIN-INDUCED ENHANCEMENT OF ANGIOTENSINOGEN SYNTHESIS IN THE LIVER - DECREASED RESPONSE FOLLOWING REPEATED ENDOTOXIN EXPOSURE

To understand the mechanisms responsible for lipopolysaccharide (LPS)- induced enhancement of angiotensinogen synthesis in the liver, studies were carried out in rats with repeated doses of LPS. The administrati on of sublethal dose (50 mug, i.p.) of LPS to rats resulted in increas e in serum levels of tumor necrosis factor (TNF) and interleukin-6 (IL -6), which attained their maximal levels by 1 and 2-4 h, respectively. Serum levels of angiotensinogen and alpha2-macroglobulin, a typical a cute-phase protein in the rat, were also increased by a primary LPS ch allenge, and their maximal levels for the formation of TNF and IL-6 we re delayed with peaks at 12 and 48 h, respectively. Repeated i.p. admi nistration of LPS (50 mug/d) for 5 consecutive days induced a hyporesp onsiveness to its subsequent administration in terms of increasing ser um TNF, IL-6 and alpha2-macroglobulin. In these LPS-tolerant rats, eit her LPS-induced elevation of angiotensinogen concentration in serum or angiotensinogen mRNA levels in liver was completely eliminated. Angio tensinogen synthesis in rat hepatoma H4 cells was enhanced in vitro by the addition of sera which had been collected 2 or 4 h after a primar y injection of LPS, while not by sera collected from LPS-pretreated ra ts after a secondary LPS exposure. These results indicate that LPS-ind uced enhancement of angiotensinogen synthesis in the liver is desensit ized in rats after repetitive LPS exposure, presumably by the failure of LPS-induced IL-6 production.