Inhibiting Glycogen Synthase Kinase 3β 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.