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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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Related in: MedlinePlus

Exacerbation of the innate immune response by i.c.v. spermine administration. Mice received a 100-nmol i.c.v. bolus of spermine or vehicle solution 5 min before the i.p. LPS challenge, and were killed 6 h after injection time. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections hybridized with either toll-like receptor 2 (TLR2) or tumor necrosis factor α (TNF-α) cRNA probe. Please note the robust and widespread hybridization signal for both transcripts in the brain of mice that received both i.c.v. spermine and i.p. LPS. The plotting graphs depict the semi-quantitative analysis of hybridization signal performed as described in Materials and methods. Data are means (± SEM) percentage of the control group (vehicle i.c.v/vehicle i.p.). BV, blood vessels; AP, area postrema; ME, median eminence; SFO, subfornical organ. †, significantly different (P < 0.05) from the other groups. ††, significantly different (P < 0.05) from both groups of vehicle-treated mice.
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fig5: Exacerbation of the innate immune response by i.c.v. spermine administration. Mice received a 100-nmol i.c.v. bolus of spermine or vehicle solution 5 min before the i.p. LPS challenge, and were killed 6 h after injection time. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections hybridized with either toll-like receptor 2 (TLR2) or tumor necrosis factor α (TNF-α) cRNA probe. Please note the robust and widespread hybridization signal for both transcripts in the brain of mice that received both i.c.v. spermine and i.p. LPS. The plotting graphs depict the semi-quantitative analysis of hybridization signal performed as described in Materials and methods. Data are means (± SEM) percentage of the control group (vehicle i.c.v/vehicle i.p.). BV, blood vessels; AP, area postrema; ME, median eminence; SFO, subfornical organ. †, significantly different (P < 0.05) from the other groups. ††, significantly different (P < 0.05) from both groups of vehicle-treated mice.

Mentions: The next series of experiments tested the effects of spermine on the innate immune response in the CNS. In contrast to DFMO, intracerebroventricular (i.c.v.) spermine administration exacerbated the effects of LPS on TLR2 and TNF-α gene expression in the mouse brain (Fig. 5). Animals that received the intracerebral spermine treatment before the systemic LPS injection exhibited a profound transcriptional activation of TLR2 in the chp, CVOs, leptomeninges, microcapillaries, and within small, scattered cells across the cerebral tissue (Fig. 5, second left column). This was also the case for the pro-inflammatory cytokine TNF-α, especially within small, scattered cells in the brain parenchyma. Indeed, TNF-α–expressing cells were clearly more numerous and widely spread throughout the CNS of mice that were killed 6 h after being injected with spermine before the endotoxin (right column). TLR2 and TNF-α mRNA levels increased by 560 and 35%, respectively, in response to spermine/LPS treatment when compared with the signal intensity quantified in the cerebral tissue of mice challenged only with the bacterial endotoxin (Fig. 5, bottom). Nevertheless, the polyamine is not by itself an immune stimulus for microglial cells because the treatment with spermine alone failed to trigger TLR2 and TNF-α gene expression in the mouse CNS (Fig. 5, bottom).


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)

Exacerbation of the innate immune response by i.c.v. spermine administration. Mice received a 100-nmol i.c.v. bolus of spermine or vehicle solution 5 min before the i.p. LPS challenge, and were killed 6 h after injection time. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections hybridized with either toll-like receptor 2 (TLR2) or tumor necrosis factor α (TNF-α) cRNA probe. Please note the robust and widespread hybridization signal for both transcripts in the brain of mice that received both i.c.v. spermine and i.p. LPS. The plotting graphs depict the semi-quantitative analysis of hybridization signal performed as described in Materials and methods. Data are means (± SEM) percentage of the control group (vehicle i.c.v/vehicle i.p.). BV, blood vessels; AP, area postrema; ME, median eminence; SFO, subfornical organ. †, significantly different (P < 0.05) from the other groups. ††, significantly different (P < 0.05) from both groups of vehicle-treated mice.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172794&req=5

fig5: Exacerbation of the innate immune response by i.c.v. spermine administration. Mice received a 100-nmol i.c.v. bolus of spermine or vehicle solution 5 min before the i.p. LPS challenge, and were killed 6 h after injection time. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections hybridized with either toll-like receptor 2 (TLR2) or tumor necrosis factor α (TNF-α) cRNA probe. Please note the robust and widespread hybridization signal for both transcripts in the brain of mice that received both i.c.v. spermine and i.p. LPS. The plotting graphs depict the semi-quantitative analysis of hybridization signal performed as described in Materials and methods. Data are means (± SEM) percentage of the control group (vehicle i.c.v/vehicle i.p.). BV, blood vessels; AP, area postrema; ME, median eminence; SFO, subfornical organ. †, significantly different (P < 0.05) from the other groups. ††, significantly different (P < 0.05) from both groups of vehicle-treated mice.
Mentions: The next series of experiments tested the effects of spermine on the innate immune response in the CNS. In contrast to DFMO, intracerebroventricular (i.c.v.) spermine administration exacerbated the effects of LPS on TLR2 and TNF-α gene expression in the mouse brain (Fig. 5). Animals that received the intracerebral spermine treatment before the systemic LPS injection exhibited a profound transcriptional activation of TLR2 in the chp, CVOs, leptomeninges, microcapillaries, and within small, scattered cells across the cerebral tissue (Fig. 5, second left column). This was also the case for the pro-inflammatory cytokine TNF-α, especially within small, scattered cells in the brain parenchyma. Indeed, TNF-α–expressing cells were clearly more numerous and widely spread throughout the CNS of mice that were killed 6 h after being injected with spermine before the endotoxin (right column). TLR2 and TNF-α mRNA levels increased by 560 and 35%, respectively, in response to spermine/LPS treatment when compared with the signal intensity quantified in the cerebral tissue of mice challenged only with the bacterial endotoxin (Fig. 5, bottom). Nevertheless, the polyamine is not by itself an immune stimulus for microglial cells because the treatment with spermine alone failed to trigger TLR2 and TNF-α gene expression in the mouse CNS (Fig. 5, bottom).

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