Article

Glycogen synthase kinase-3β (GSK3β) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice

Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, BBRB 258/5, Birmingham, AL 35294-2170, United States
Molecular Immunology DOI:10.1016/j.molimm.2008.08.281

ABSTRACT Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia.

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    Article: Kinase activity profiling of pneumococcal pneumonia.
    Arie J Hoogendijk, Sander H Diks, Tom van der Poll, Maikel P Peppelenbosch, Catharina W Wieland
    [show abstract] [hide abstract]
    ABSTRACT: Pneumonia represents a major health burden. Previous work demonstrated that although the induction of inflammation is important for adequate host defense against pneumonia, an inability to regulate the host's inflammatory response within the lung later during infection can be detrimental. Intracellular signaling pathways commonly rely on activation of kinases, and kinases play an essential role in the regulation of the inflammatory response of immune cells. Pneumonia was induced in mice via intranasal instillation of Streptococcus (S.) pneumoniae. Kinomics peptide arrays, exhibiting 1024 specific consensus sequences for protein kinases, were used to produce a systems biology analysis of cellular kinase activity during the course of pneumonia. Several differences in kinase activity revealed by the arrays were validated in lung homogenates of individual mice using western blot. We identified cascades of activated kinases showing that chemotoxic stress and a T helper 1 response were induced during the course of pneumococcal pneumonia. In addition, our data point to a reduction in WNT activity in lungs of S. pneumoniae infected mice. Moreover, this study demonstrated a reduction in overall CDK activity implying alterations in cell cycle biology. This study utilizes systems biology to provide insight into the signaling events occurring during lung infection with the common cause of community acquired pneumonia, and may assist in identifying novel therapeutic targets in the treatment of bacterial pneumonia.
    PLoS ONE 01/2011; 6(4):e18519. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

anti-inflammatory cytokine IL-10
 
bioterrorism agent
 
causative agent
 
F. tularensis LVS
 
F. tularensis LVS infection
 
F. tularensis LVS-induced cytokine response
 
F. tularensis results
 
Glycogen synthase kinase-3β
 
GSK3β inhibition
 
IFN-γ potentiated F. tularensis LVS-induced cytokine production
 
infected animals
 
key regulatory
 
modulating inflammatory responses
 
murine peritoneal macrophages induced
 
novel therapeutic approach
 
pro-inflammatory cytokine IL-6
 
serine/threonine protein kinase
 
significant decrease
 
TLR2 dependent phosphorylation
 
transcription factors NF-κB
 

Ping Zhang