Regulatory role of GSK-3 β on NF-B, nitric oxide, and TNF-α in group A streptococcal infection

Group A streptococcus (GAS) imposes a great burden on humans. Efforts to minimize the associated morbidity and mortality represent a critical issue. Glycogen synthase kinase-3β (GSK-3β) is known to regulate inflammatory response in infectious diseases. However, the regulation of GSK-3β in GAS infection is still unknown. The present study investigates the interaction between GSK-3β, NF-B, and possible related inflammatory mediators in vitro and in a mouse model. The results revealed that GAS could activate NF-B, followed by an increased expression of inducible nitric oxide synthase (iNOS) and NO production in a murine macrophage cell line. Activation of GSK-3β occurred after GAS infection, and inhibition of GSK-3β reduced iNOS expression and NO production. Furthermore, GSK-3β inhibitors reduced NF-B activation and subsequent TNF-α production, which indicates that GSK-3β acts upstream of NF-B in GAS-infected macrophages. Similar to the in vitro findings, administration of GSK-3β inhibitor in an air pouch GAS infection mouse model significantly reduced the level of serum TNF-α and improved the survival rate. The inhibition of GSK-3β to moderate the inflammatory effect might be an alternative therapeutic strategy against GAS infection.