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

T. F. Tay, M. Maheran, S. L. Too, Hasidah Mohd. Sidek, G. Ismail, Mohammed Noor Embi

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)551-567
Number of pages17
JournalTropical Biomedicine
Volume29
Issue number4
Publication statusPublished - Dec 2012

Fingerprint

Burkholderia pseudomallei
Glycogen Synthase Kinase 3
Cytokines
Interleukin 1 Receptor Antagonist Protein
Spleen
Burkholderia Infections
Interleukin-1
Interleukin-10
Melioidosis
Lung
Liver
Anti-Inflammatory Agents
Bacteria
Bacterial Load
Lethal Dose 50
Serum
Sepsis
Soil

ASJC Scopus subject areas

  • Infectious Diseases
  • Parasitology

Cite this

Glycogen synthase kinase-3β inhibition improved survivability of mice infected with Burkholderia pseudomallei. / Tay, T. F.; Maheran, M.; Too, S. L.; Mohd. Sidek, Hasidah; Ismail, G.; Embi, Mohammed Noor.

In: Tropical Biomedicine, Vol. 29, No. 4, 12.2012, p. 551-567.

Research output: Contribution to journalArticle

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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.",
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