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Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

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Effects of LPS and DFMO treatments in the brain ODC activity. ODC activity was determined as described in Materials and methods. Data are mean ± SEM (bars) values of four animals. †, significantly different (P < 0.005) from all the other groups of mice.
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fig3: Effects of LPS and DFMO treatments in the brain ODC activity. ODC activity was determined as described in Materials and methods. Data are mean ± SEM (bars) values of four animals. †, significantly different (P < 0.005) from all the other groups of mice.

Mentions: The ODC protein is a particular enzyme well known for its extremely short half-life and its narrowly controlled transcription, translation, and activity. To ensure that LPS-induced increase in ODC gene expression was really associated with putrescine biosynthesis, ODC activity was measured in one hemisphere of each control and treated mouse (Fig. 3). In accordance with other reports, a low level of ODC activity was found in the brain of control mice (Kilpelainen et al., 2001). Cerebral ODC activity was not significantly different between control mice and those that were treated with DFMO. However, ODC activity was strongly induced by sixfold 3 h after a single systemic injection of LPS, which indicates that the latter is able to increase the biosynthesis of putrescine in the brain. The enzymatic activity was reduced by 50% in mice that had access to DFMO in their tap water for 2 d before the systemic LPS challenge. These data demonstrate the ability of DFMO to cross the blood-brain barrier (BBB) and inhibit the ODC protein within the brain.


Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Effects of LPS and DFMO treatments in the brain ODC activity. ODC activity was determined as described in Materials and methods. Data are mean ± SEM (bars) values of four animals. †, significantly different (P < 0.005) from all the other groups of mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172794&req=5

fig3: Effects of LPS and DFMO treatments in the brain ODC activity. ODC activity was determined as described in Materials and methods. Data are mean ± SEM (bars) values of four animals. †, significantly different (P < 0.005) from all the other groups of mice.
Mentions: The ODC protein is a particular enzyme well known for its extremely short half-life and its narrowly controlled transcription, translation, and activity. To ensure that LPS-induced increase in ODC gene expression was really associated with putrescine biosynthesis, ODC activity was measured in one hemisphere of each control and treated mouse (Fig. 3). In accordance with other reports, a low level of ODC activity was found in the brain of control mice (Kilpelainen et al., 2001). Cerebral ODC activity was not significantly different between control mice and those that were treated with DFMO. However, ODC activity was strongly induced by sixfold 3 h after a single systemic injection of LPS, which indicates that the latter is able to increase the biosynthesis of putrescine in the brain. The enzymatic activity was reduced by 50% in mice that had access to DFMO in their tap water for 2 d before the systemic LPS challenge. These data demonstrate the ability of DFMO to cross the blood-brain barrier (BBB) and inhibit the ODC protein within the brain.

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

Show MeSH
Related in: MedlinePlus