Decreased acid-labile subunit (ALS) levels by endotoxin in vivo and by interleukin-1beta in vitro.
The production by the liver of the three subunits of the growth hormone (GH)-dependent 150 kDa complex (IGF-I, IGF-binding protein-3 and acid-labile subunit or ALS) is primarily under the control of GH. Recent data have shown that, besides GH, endotoxin (LPS) and cytokines may regulate the liver IGF-I gene. To investigate the potential regulation of ALS by LPS, we measured serum ALS by immunoblot, 5 and 10 h after IP injection of LPS (250 or 750 microg/100 g BW vs saline), in 4-week-old female Wistar rats (four per group). Ten hours after injection, serum ALS levels were reduced by 57% (delta%) with the lower dose (P<0.05) and by 81% with the higher dose (P<0.01) by comparison with saline-treated rats. The decrease in ALS levels in response to LPS was not prevented by exogenous GH. To investigate the role of interleukin (IL)-1beta in the regulation of ALS, primary cultured rat hepatocytes were exposed to increasing concentrations of IL-1beta. Cell exposure to IL-1beta markedly decreased both basal and GH-stimulated ALS levels (-70%; P<0.01) in a dose-dependent fashion, with the half-maximal inhibitory effect at concentrations of 0.1 ng/ml. Our results show that endotoxin induces a rapid decline in circulating ALS that is potentially mediated through IL-1beta. By limiting the formation of the 150 kDa complex, this reduction in circulating ALS might contribute to the rapid decline in serum IGF-I observed in sepsis.
Barreca
A
A
Department of Endocrinology and Metabolism, University of Genova, Italy. barreca@csita.unige.it
Ketelslegers
J M
JM
Arvigo
M
M
Minuto
F
F
Thissen
J P
JP
D000818:Animals; D002352:Carrier Proteins / Q000097:blood*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D013006:Growth Hormone / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000378:metabolism*; D012741:Sexual Maturation
D002352:Carrier Proteins; D016207:Cytokines; D004731:Endotoxins; D006023:Glycoproteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D013006:Growth Hormone