Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3

Speaker: 江承堯                       Time: 2005/09/21 14:00~15:00

Commentator: 謝奇璋 醫師              Place: Room D602

Abstract:

Glycogen synthase kinase 3 (GSK3), a central enzyme in many metabolism pathways, is involved in cell apoptosis and cell cycle regulation.¹ However, there is no report regarding the involvement of GSK3 in Toll-like receptor (TLR) signalling pathway. In this study, the authors showed that GSK3 differentially regulated TLR-mediated pro-inflammatory and anti-inflammatory cytokine production.² Peripheral blood mononuclear cells from healthy donors showed GSK3 phosphorylation after lipopolysaccharide (LPS) stimulation, suggesting GSK3 might be involved in TLR4 signalling pathway. LPS induced PI3K-Akt-GSK3 pathway and pro-inflammatory cytokine production including IL-12, IL-6 and TNF. However, inhibition of GSK3 reduced the pro-inflammatory cytokine production and increased the anti-inflammatory cytokine IL-10 production. The underlying mechanism responsible for the differential regulation of GSK3 on pro- and anti-inflammatory cytokine production were related to the binding of transcription factors CREB (cyclic AMP responsive element) and NF-κB with CBP (CREB binding protein, co-activator of transcription factor). Without GSK3 inhibitors or GSK3 siRNA, the activity of CREB was weaker than NF-kB because of CBP binding with NF-kB. After treatment with GSK3 inhibitor or GSK3 siRNA, the CREB activity was augmented due to the increased binding with CBP. This effect was further evidenced in the murine model. GSK3 inhibitor suppressed the pro-inflammatory cytokine response and provided protection from endotoxin shock when mice were intravenously injected with lethal dose of LPS. These results demonstrate that GSK3 plays a modulatory role in the inflammatory response.

References:

1. Frame, S. and Cohen, P. 2001. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1-16

2. Martin, M. et al. 2005. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature 6, 777-784