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