Effects of cytokine antagonists on the hepatic acute-phase response.
Endotoxin-induced hepatic acute-phase protein synthesis has been thought to be primarily regulated through cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). Previously, it was found that a 23-kDa murine acute-phase protein, the lipopolysaccharide (LPS)-induced protein (LIP), was synthesized following treatment of hepatocytes in vitro with LPS. Since this protein was also induced by IL-1 and IL-6, the present studies were undertaken to determine if the effect of endotoxin was mediated through these cytokines. Primary cultures of murine hepatocytes were treated with LPS, IL-1, IL-6, or an LPS-stimulated macrophage supernatant in the presence or absence of the IL-1 receptor antagonist (IL-1 RA) and/or an anti-IL-6 antibody. The cells were then radiolabeled with [35S]methionine. LIP was detected by electrophoresis and autoradiography of the secreted proteins. In vitro, IL-1 RA completely inhibited the stimulation of LIP synthesis elicited by IL-1 and the macrophage supernatant, but did not affect LPS-stimulated synthesis of this protein. The anti-IL-6 antibody inhibited IL-6-triggered synthesis of LIP, but had no effect on LPS-stimulated synthesis. Hepatocytes isolated from mice treated in vivo with both IL-1 RA and LPS synthesized LIP to the same degree as hepatocytes isolated from mice treated with LPS alone. LPS-stimulated synthesis of LIP in vitro does not require IL-1 or IL-6 as an obligatory intermediate. These results are consistent with the hypothesis that endotoxin can directly stimulate hepatocyte acute-phase protein synthesis in the absence of cytokines.
Mazuski
J E
JE
Department of Surgery, DVA Medical Center, St. Louis, Missouri 63106, USA.
Tolman
K
K
Shapiro
M J
MJ
D000209:Acute-Phase Proteins / Q000096:biosynthesis*; D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005260:Female; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012097:Repressor Proteins / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D000209:Acute-Phase Proteins; D000906:Antibodies; D022782:CCAAT-Enhancer-Binding Protein-beta; D017077:Culture Media, Conditioned; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012097:Repressor Proteins; D012795:Sialoglycoproteins; D000093242:Interleukin-6 Inhibitors; C507764:Il1rn protein, mouse