Inhibition of GSK3 Attenuates the Intracellular Multiplication of Burkholderia pseudomallei and Modulates the Inflammatory Response in Infected Macrophages and A549 Epithelial Lung Cells

Pramila Maniam, Aishah Farliani Shiratirat, Hasidah Mohd. Sidek, Ghazally Ismail, Mohammed Noor Embi

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6 Citations (Scopus)

Abstract

Burkholderia pseudomallei, the causative agent of melioidosis, is an intracellular pathogen capable of invading and multiplying in both phagocytic and non-phagocytic cells. Infection results in an inflammatory response involving production of both pro-and anti-inflammatory cytokines. The cellular mechanism regulating this response, believed to play an important role in the pathogenesis of meliodoisis, is not fully understood. In recent years, glycogen synthase kinase-3 (GSK3) has been shown to assume a pivotal role in regulating production of these cytokines. Bacterial infection of host cells activates Toll-like receptors (TLRs) and results in the phosphorylation of GSK3β through activation of the phosphoinositide 3-kinase (PI3K) pathway. In this study, we investigated the effects of GSK3 inhibition in regulating B. pseudomallei-induced inflammatory response in macrophages and A549 epithelial lung cells. Our results showed that infection of cells with B. pseudomallei resulted in the increase of anti-inflammatory cytokine, IL-10 and pro-inflammatory cytokine, TNF-α. Pre-treatment of infected cells with GSK3 inhibitors caused further increase in the level of IL-10 but a significant decrease in TNF-α. These changes corresponded with the detection of phosphorylated GSK3β in infected cells treated with LiCl; suggesting that modulation of inflammatory response in B. pseudomallei infection involves phosphorylation of GSK3β (Ser 9). This could explain our observations from the invasion assays that pre-treatment of B. pseudomallei-infected cells with GSK3 inhibitors resulted in decreased intracellular replication of bacteria within macrophages and A549 epithelial lung cells. In summary, our results demonstrate a regulatory function of GSK3 in the modulation of cytokine levels during B. pseudomallei infection.

Original languageEnglish
Pages (from-to)725-735
Number of pages11
JournalSains Malaysiana
Volume42
Issue number6
Publication statusPublished - Jun 2013

Fingerprint

Burkholderia pseudomallei
Glycogen Synthase Kinase 3
Epithelial Cells
Macrophages
Lung
Cytokines
Burkholderia Infections
Interleukin-10
Anti-Inflammatory Agents
Phosphorylation
Melioidosis
1-Phosphatidylinositol 4-Kinase
A549 Cells
Toll-Like Receptors
Infection
Bacterial Infections
Bacteria

Keywords

  • Burkholderia pseudomallei
  • Glycogen synthase kinase-3
  • Inflammation
  • Macrophage
  • Melioidosis

ASJC Scopus subject areas

  • General

Cite this

@article{f336735a4f4e4dc486ad54bd180ff01b,
title = "Inhibition of GSK3 Attenuates the Intracellular Multiplication of Burkholderia pseudomallei and Modulates the Inflammatory Response in Infected Macrophages and A549 Epithelial Lung Cells",
abstract = "Burkholderia pseudomallei, the causative agent of melioidosis, is an intracellular pathogen capable of invading and multiplying in both phagocytic and non-phagocytic cells. Infection results in an inflammatory response involving production of both pro-and anti-inflammatory cytokines. The cellular mechanism regulating this response, believed to play an important role in the pathogenesis of meliodoisis, is not fully understood. In recent years, glycogen synthase kinase-3 (GSK3) has been shown to assume a pivotal role in regulating production of these cytokines. Bacterial infection of host cells activates Toll-like receptors (TLRs) and results in the phosphorylation of GSK3β through activation of the phosphoinositide 3-kinase (PI3K) pathway. In this study, we investigated the effects of GSK3 inhibition in regulating B. pseudomallei-induced inflammatory response in macrophages and A549 epithelial lung cells. Our results showed that infection of cells with B. pseudomallei resulted in the increase of anti-inflammatory cytokine, IL-10 and pro-inflammatory cytokine, TNF-α. Pre-treatment of infected cells with GSK3 inhibitors caused further increase in the level of IL-10 but a significant decrease in TNF-α. These changes corresponded with the detection of phosphorylated GSK3β in infected cells treated with LiCl; suggesting that modulation of inflammatory response in B. pseudomallei infection involves phosphorylation of GSK3β (Ser 9). This could explain our observations from the invasion assays that pre-treatment of B. pseudomallei-infected cells with GSK3 inhibitors resulted in decreased intracellular replication of bacteria within macrophages and A549 epithelial lung cells. In summary, our results demonstrate a regulatory function of GSK3 in the modulation of cytokine levels during B. pseudomallei infection.",
keywords = "Burkholderia pseudomallei, Glycogen synthase kinase-3, Inflammation, Macrophage, Melioidosis",
author = "Pramila Maniam and Shiratirat, {Aishah Farliani} and {Mohd. Sidek}, Hasidah and Ghazally Ismail and Embi, {Mohammed Noor}",
year = "2013",
month = "6",
language = "English",
volume = "42",
pages = "725--735",
journal = "Sains Malaysiana",
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T1 - Inhibition of GSK3 Attenuates the Intracellular Multiplication of Burkholderia pseudomallei and Modulates the Inflammatory Response in Infected Macrophages and A549 Epithelial Lung Cells

AU - Maniam, Pramila

AU - Shiratirat, Aishah Farliani

AU - Mohd. Sidek, Hasidah

AU - Ismail, Ghazally

AU - Embi, Mohammed Noor

PY - 2013/6

Y1 - 2013/6

N2 - Burkholderia pseudomallei, the causative agent of melioidosis, is an intracellular pathogen capable of invading and multiplying in both phagocytic and non-phagocytic cells. Infection results in an inflammatory response involving production of both pro-and anti-inflammatory cytokines. The cellular mechanism regulating this response, believed to play an important role in the pathogenesis of meliodoisis, is not fully understood. In recent years, glycogen synthase kinase-3 (GSK3) has been shown to assume a pivotal role in regulating production of these cytokines. Bacterial infection of host cells activates Toll-like receptors (TLRs) and results in the phosphorylation of GSK3β through activation of the phosphoinositide 3-kinase (PI3K) pathway. In this study, we investigated the effects of GSK3 inhibition in regulating B. pseudomallei-induced inflammatory response in macrophages and A549 epithelial lung cells. Our results showed that infection of cells with B. pseudomallei resulted in the increase of anti-inflammatory cytokine, IL-10 and pro-inflammatory cytokine, TNF-α. Pre-treatment of infected cells with GSK3 inhibitors caused further increase in the level of IL-10 but a significant decrease in TNF-α. These changes corresponded with the detection of phosphorylated GSK3β in infected cells treated with LiCl; suggesting that modulation of inflammatory response in B. pseudomallei infection involves phosphorylation of GSK3β (Ser 9). This could explain our observations from the invasion assays that pre-treatment of B. pseudomallei-infected cells with GSK3 inhibitors resulted in decreased intracellular replication of bacteria within macrophages and A549 epithelial lung cells. In summary, our results demonstrate a regulatory function of GSK3 in the modulation of cytokine levels during B. pseudomallei infection.

AB - Burkholderia pseudomallei, the causative agent of melioidosis, is an intracellular pathogen capable of invading and multiplying in both phagocytic and non-phagocytic cells. Infection results in an inflammatory response involving production of both pro-and anti-inflammatory cytokines. The cellular mechanism regulating this response, believed to play an important role in the pathogenesis of meliodoisis, is not fully understood. In recent years, glycogen synthase kinase-3 (GSK3) has been shown to assume a pivotal role in regulating production of these cytokines. Bacterial infection of host cells activates Toll-like receptors (TLRs) and results in the phosphorylation of GSK3β through activation of the phosphoinositide 3-kinase (PI3K) pathway. In this study, we investigated the effects of GSK3 inhibition in regulating B. pseudomallei-induced inflammatory response in macrophages and A549 epithelial lung cells. Our results showed that infection of cells with B. pseudomallei resulted in the increase of anti-inflammatory cytokine, IL-10 and pro-inflammatory cytokine, TNF-α. Pre-treatment of infected cells with GSK3 inhibitors caused further increase in the level of IL-10 but a significant decrease in TNF-α. These changes corresponded with the detection of phosphorylated GSK3β in infected cells treated with LiCl; suggesting that modulation of inflammatory response in B. pseudomallei infection involves phosphorylation of GSK3β (Ser 9). This could explain our observations from the invasion assays that pre-treatment of B. pseudomallei-infected cells with GSK3 inhibitors resulted in decreased intracellular replication of bacteria within macrophages and A549 epithelial lung cells. In summary, our results demonstrate a regulatory function of GSK3 in the modulation of cytokine levels during B. pseudomallei infection.

KW - Burkholderia pseudomallei

KW - Glycogen synthase kinase-3

KW - Inflammation

KW - Macrophage

KW - Melioidosis

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