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 administration of sublethal dose (50 micrograms, i.p.) of LPS to rats resulted in increase in serum levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6), which attained their maximal levels by 1 and 2-4h, respectively. Serum levels of angiotensinogen and alpha 2-macroglobulin, a typical acute-phase protein in the rat, were also increased by a primary LPS challenge, and their maximal levels for the formation of TNF and IL-6 were delayed with peaks at 12 and 48 h, respectively. Repeated i.p. administration of LPS (50 micrograms/d) for 5 consecutive days induced a hyporesponsiveness to its subsequent administration in terms of increasing serum TNF, IL-6 and alpha 2-macroglobulin. In these LPS-tolerant rats, either LPS-induced elevation of angiotensinogen concentration in serum or angiotensinogen mRNA levels in liver was completely eliminated. Angiotensinogen 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 primary injection of LPS, while not by sera collected from LPS-pretreated rats after a secondary LPS exposure. These results indicate that LPS-induced enhancement of angiotensinogen synthesis in the liver is desensitized in rats after repetitive LPS exposure, presumably by the failure of LPS-induced IL-6 production.
Takano
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Japan.
Yokoyama
K
K
Yayama
K
K
Itoh
N
N
Okamoto
H
H
D000808:Angiotensinogen / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004731:Endotoxins / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins; D000808:Angiotensinogen