Inhibiting glycogen synthase kinase 3beta in sepsis.
The serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in the regulation of many cell functions, but its role in the regulation of the inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by endotoxaemia or severe inflammation in the rat. Rats received either intravenous Escherichia coli lipopolysaccharide (LPS) (6 mg/kg) or LPS (1mg/kg) plus Staphylococcus aureus peptidoglycan (PepG) (0.3mg/kg) or their vehicle (saline). The GSK-3p1 inhibitors TDZD-8, SB415286 (both 1mg/kg, i.v.), and SB216763 (0.6 mg/kg i.v.), or vehicle (10% dimethyl sulfoxide) were administered 30 min before LPS or LPS/PepG. Both endotoxaemia and co-administration of LPS/PepG resulted in multiple organ injury and dysfunction. The GSK-3beta inhibitors attenuated the organ injury/dysfunction caused by LPS or LPS/PepG. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor (NF)-kappaB subunit p65 and the mRNA expression of NF-kappaB-dependent pro-inflammatory mediators, but had no effect on the NF-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in NF-kappaB p65 activity caused by interleukin (IL)1 in human e mbryonic kidney cells in vitro. We propose that GSK-3beta inhibition may be useful in the therapy of sepsis, shock and other diseases associated with local or systemic inflammation.
Dugo
Laura
L
Centre for Experimental Medicine, Nephrology and Critical Care Medicine, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London ECIM 6BQ, UK.
Collin
Marika
M
Allen
David A
DA
Patel
Nimesh S A
NS
Bauer
Inge
I
Mervaala
Eero
E
Louhelainen
Marjut
M
Foster
Simon J
SJ
Yaqoob
Muhammad M
MM
Thiemermann
Christoph
C
D000410:Alanine Transaminase / Q000097:blood; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D010457:Peptidoglycan / Q000008:administration & dosage; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D013830:Thiadiazoles / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000627:Aminophenols; D004791:Enzyme Inhibitors; D007211:Indoles; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008301:Maleimides; D010457:Peptidoglycan; C417521:SB 216763; D013830:Thiadiazoles; D051996:Transcription Factor RelA; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3