Cytokines in the Central Nervous System: Regulatory Roles in Neuronal Function, Cell Death and Repair

Sei, Yoshitatsu; Vitkoviç, Ljubiša; Yokoyama, Mitsuo

doi:10.1159/000096881

Cited by 77 publications

(51 citation statements)

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“…Interleukin-1␤ (IL-1␤) 3 has been proposed as a novel neuromodulator involved in the communication between glia and neurons (1)(2)(3)(4), opening up new perspective in the current view of brain behavior. This cytokine, locally produced by glial cells as a consequence of CNS diseases and/or in response to neuronal activities (4), exerts a profound impact on neuronal functionality through a specific receptor.…”

mentioning

confidence: 99%

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Viviani¹,

Gardoni²,

Bartesaghi

et al. 2006

Journal of Biological Chemistry

108

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Interleukin-1␤ is a proinflammatory cytokine implicated under pathological conditions involving NMDA receptor activation, including the AIDS dementia complex (HAD). No information is available on the molecular mechanisms recruited by native interleukin-1␤ produced under this type of condition. Using a sandwich co-culture of primary hippocampal neurons and glia, we investigated whether native interleukin-1␤ released by HIV-gp120-activated glia (i) affects NMDAR functions and (ii) the relevance on neuronal spine density and survival, two specific traits of HAD. Increased phosphorylation of NR2B Tyr-1472 was observed after 24 h of exposure of neurons to 600 pM gp120. This effect occurred only when neurons were treated in the presence of glial cells and was abolished by the interleukin-1 receptor antagonist (IL-1ra). Gp120-induced phosphorylation of NR2B resulted in a sustained elevation of intracellular Ca 2؉ in neurons and in a significant increase of NR2B binding to PSD95. Increased intracellular Ca2؉ was prevented by 10 M ifenprodil, that selectively inhibits receptors containing the NR2B, by interleukin-1ra and by Ca-pYEEIE, a Src family SH2 inhibitor peptide. These last two inhibitors, prevented also NR2B binding to PSD95. Finally, gp120 reduced by 35% of the total PSD95 positive spine density after 48 h of treatment and induced by 30% of the neuronal death. Again, both of these effects were blocked by Ca-pYEEIE. Altogether, our data show that gp120 releasing interleukin-1␤ from glia increases tyrosine phosphorylation of NMDAR. Thus, tyrosine phosphorylation may contribute to the sensitization of the receptor increasing its function and synaptic localization. Both of these effects are relevant for neurodegeneration. Interleukin-1␤ (IL-1␤)3 has been proposed as a novel neuromodulator involved in the communication between glia and neurons (1-4), opening up new perspective in the current view of brain behavior. This cytokine, locally produced by glial cells as a consequence of CNS diseases and/or in response to neuronal activities (4), exerts a profound impact on neuronal functionality through a specific receptor. So far, IL-1␤ has been implicated in the exacerbation of neuronal damage caused by excitotoxic, ischemic, traumatic brain injury (5, 6), and viral infection (AIDS dementia complex: HAD) (7-9), in seizures (10) as well as in physiological events such as long-term potentiation (11, 12), sleep (13), memory consolidation (14, 15), and pain (16). Although IL-1␤ may offer exciting potential in the discovery of novel targets to modulate brain behavior, the biochemical pathways specifically recruited in neurons by this cytokine have not been explored in detail.Recombinant IL-1␤ potentiates calcium response and neuronal death achieved through NMDA receptor activation in primary hippocampal neurons by increasing phosphorylation of NR2B tyrosine 1472 (17). Tyrosine phosphorylation of NR2 subunits has been involved in NMDAR channel gating, protection of NR2 subunits against degradation by calpain, assembly with sig...

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confidence: 99%

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Viviani¹,

Gardoni²,

Bartesaghi

et al. 2006

Journal of Biological Chemistry

108

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“…To date, virtually all known cytokines or their receptors have been sought (and found) in many CNS cells, including neurons (1)(2)(3)(4)(5)(6)(7). Many experimental approaches have been used to define the extent to which cytokines and their receptors are expressed in nervous system tissues and the extent to which these tissues respond to cytokines.…”

mentioning

confidence: 99%

“…Many experimental approaches have been used to define the extent to which cytokines and their receptors are expressed in nervous system tissues and the extent to which these tissues respond to cytokines. These include in situ hybridization and Northern blot analysis for mRNA expression; radioimmunoassay and ELISA for peptide content; autoradiographic localization of receptors by radiolabeled cytokine binding in brain slices; immunohistochemistry to define cytokine pathways in the nervous system; neuropeptide secretion by brain explants, primary cell cultures, or cell lines exposed to cytokines and cytokine production by brain explants, primary cell cultures, or cell lines exposed to neuropeptides (7). Table I shows the extent to which these molecules have been identified in neurons, astrocytes, oligodendrocytes, and microglia by these approaches.…”

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confidence: 99%

Neural-immune interactions in health and disease.

Sternberg¹

1997

J. Clin. Invest.

326

163

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“…1 However, as seen with inflammatory cytokines, CSF are produced during infection, 2 exist in the brain as well as their receptors, 3 and cross the blood-brain barrier. 4 Although most inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNFa), are reported to promote non-REM sleep, 5 no study has examined whether CSF affect sleep.…”

Section: Introductionmentioning

confidence: 99%

Colony‐stimulating factors in rapid eye movement sleep and non‐rapid eye movement sleep regulation

Kimura

Kodama

Honda

et al. 1999

Psychiatry Clin Neurosci

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Although several cytokines are known to be somnogenic, no study has been conducted to examine whether colony-stimulating factors (CSF) affect sleep. Therefore, we studied the effects of granulocyte-macrophage CSF (GM-CSF) and macrophage CSF (M-CSF) on sleep in rats and their possible mechanism of action. At the dose of 10 pmol, GM-CSF or M-CSF significantly increased both non-rapid eye movement and rapid eye movement (REM) sleep or REM sleep only when infused intracerebroventricularly during the dark period. When injected locally in the hypothalamus, GM-CSF and M-CSF increased nitric oxide (NO) production. Thus, NOergic neural signals in the hypothalamus may take part in the somnogenic action of CSF.

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Cytokines in the Central Nervous System: Regulatory Roles in Neuronal Function, Cell Death and Repair

Cited by 77 publications

References 0 publications

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Interleukin-1β Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors

Neural-immune interactions in health and disease.

Colony‐stimulating factors in rapid eye movement sleep and non‐rapid eye movement sleep regulation

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