Glycogen synthase kinase-3 beta inhibition improved survivability of mice infected with Burkholderia pseudomallei

The disease melioidosis, caused by the soil bacteria Burkholderia pseudomallei, often manifests as acute septicemia with high fatality. Glycogen synthase kinase-3 beta (GSK3 beta)plays a key role during the inflammatory response induced by bacteria. We used a murine model of acute melioidosis to investigate the effects of LiCl, a GSK3 inhibitor on experimental animal survivability as well as TNF-alpha, IL-1 beta, IFN-gamma, IL-10 and IL-1Ra cytokine levels in blood, lung, liver and spleen of B. pseudomallei-infected mice. Our results showed that administration of 100 mu g/g LiCl improved survivability of mice infected with 5 X LD50 of B. pseudomallei. Bacterial counts in spleen, liver and lungs of infected mice administered with LiCl were lower than non-treated controls. Our data also revealed that GSK3 beta is phosphorylated in the spleen, liver and lung of animals infected with B. pseudomallei. However in infected animals administered with LiCl, higher levels of pGSK3 were detected in the organs. Levels of proinflammatory cytokines (TNF-alpha, IL-1 beta and IFN-gamma) and anti-inflammatory cytokines (IL-10 and IL-1Ra) in sera and organs tested were elevated significantly following B. pseudomallei infection. With GSK3 beta inhibition, pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-1 beta) were significantly decreased in all the samples tested whilst the levels of anti-inflammatory cytokines, IL-10 (spleen and lung) and IL-1Ra (spleen, liver and sera) were further elevated. This study represents the first report implicating GSK3 beta in the modulation of cytokine production during B. pseudomallei infection thus reiterating the important role of GSK3 beta in the inflammatory response caused by bacterial pathogens.