title: Glycogen synthase kinase-3β inhibition improved survivability of mice infected with Burkholderia pseudomallei.
abstract: The disease melioidosis, caused by the soil bacteria Burkholderia pseudomallei,   often manifests as acute septicemia with high fatality. Glycogen synthase kinase-3β (GSK3β)   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-α, IL-1β, IFN-γ, 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 μg/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 GSK3β 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-α, IL-1β and IFN-γ) and anti-inflammatory cytokines (IL-10 and   IL-1Ra) in sera and organs tested were elevated significantly following B. pseudomallei   infection. With GSK3β inhibition, pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β) 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 GSK3β in the modulation of cytokine production   during B. pseudomallei infection thus reiterating the important role of GSK3β in the   inflammatory response caused by bacterial pathogens.
authors.affiliation: School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor D.E. Malaysia.
authors.forename: T F
authors.initials: TF
authors.lastname: Tay
authors.forename: M
authors.initials: M
authors.lastname: Maheran
authors.forename: S L
authors.initials: SL
authors.lastname: Too
authors.forename: M S
authors.initials: MS
authors.lastname: Hasidah
authors.forename: G
authors.initials: G
authors.lastname: Ismail
authors.forename: N
authors.initials: N
authors.lastname: Embi
mesh_terms: D000818:Animals; D001419:Bacteria; D058491:Bacterial Load; D001774:Blood Chemical Analysis; D016957:Burkholderia pseudomallei / Q000302:isolation & purification / Q000472:pathogenicity*; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D007155:Immunologic Factors / Q000008:administration & dosage*; D018021:Lithium Chloride / Q000008:administration & dosage*; D008099:Liver / Q000737:chemistry / Q000382:microbiology; D008168:Lung / Q000737:chemistry / Q000382:microbiology; D008297:Male; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000737:chemistry / Q000382:microbiology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride