Inhibition by recombinant human interleukin-6 of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase and of the insulin-dependent induction of glucokinase gene expression in cultured rat hepatocytes: regulation of gene transcription and messenger RNA degradation.
The influence of recombinant human interleukin-6, the major mediator of the inflammatory response in liver, on the glucagon- and insulin-dependent induction of the phosphoenolpyruvate carboxykinase and glucokinase gene, respectively, was monitored on the level of gene transcription, mRNA abundance and enzyme activity in cultured rat hepatocytes. As control markers of the interleukin-6-induced acute-phase response the mRNA levels of the acute phase proteins alpha 2-macroglobulin and beta-fibrinogen were determined. In cultured rat hepatocytes, recombinant human interleukin-6, added simultaneously with glucagon and insulin, lowered the maximal increase in glucagon-induced phosphoenolpyruvate carboxykinase mRNA levels after 2 hr and the maximal increase in glucokinase mRNA levels after 3 hr to about 30%, respectively. It inhibited the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene transcription and phosphoenolpyruvate carboxykinase enzyme activity, as well as the insulin-induced increases in glucokinase gene transcription and glucokinase enzyme activity. Recombinant human interleukin-6 increased the mRNA levels of the acute-phase proteins alpha 2-macroglobulin and beta-fibrinogen gradually over 4 to 6 hr. Recombinant human interleukin-6, added 2 hr after glucagon or 3 hr after insulin at the maximum of the hormone-induced enzyme mRNA levels, almost doubled the decay rate of phosphoenolpyruvate carboxykinase mRNA and glucokinase mRNA. The results show that interleukin-6 induced the expression of inflammatory proteins and simultaneously inhibited the hormone-induced expression of enzymes of intermediary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Christ
B
B
Institute for Biochemistry and Molecular Cell Biology, Georg-August-Universität, Göttingen, Germany.
Nath
A
A
Heinrich
P C
PC
Jungermann
K
K
D000818:Animals; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D005340:Fibrinogen / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology*; D005941:Glucokinase / Q000096:biosynthesis* / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic; D000511:alpha-Macroglobulins / Q000378:metabolism
D007328:Insulin; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000511:alpha-Macroglobulins; D005340:Fibrinogen; D005934:Glucagon; D005941:Glucokinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)