Interleukin 1 in the brain: biology, pathology and therapeutic target

Rothwell, Nancy J.; Luheshi, Giamal N.

doi:10.1016/s0166-2236(00)01661-1

Cited by 601 publications

(448 citation statements)

References 138 publications

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“…The IL-1 family comprises in addition to the agonists IL-1α and IL-1β, IL-1ra that is a selective competitive IL-1 antagonist [59]. IL-1ra prevented the IL-1β -induced suppression of the activation of Akt by BDNF, thus providing evidence that the effect of the cytokine on BDNF signal transduction is specific ( Fig.…”

Section: The Effect Of the Cytokine On Bdnf Signaling Is Specificmentioning

confidence: 94%

“…Interleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved.…”

Section: Il-1β; Bdnf; Signal Transduction; Cortical Neuronsmentioning

confidence: 99%

“…It seems that IL-1β is neurotoxic only at high concentrations and after relatively long exposure [3]. Several mechanism by which IL-1 may induce neuronal death have been proposed including the involvement of glia [59] and the regulation of NMDA receptor [39,73].Neurotrophins, such as BDNF, are important modulators for neuronal survival and functions. BDNF, a major trophic factor in the CNS, is critical for the development and survival of certain neuronal populations.…”

mentioning

confidence: 99%

“…IL-1 is linked to the loss because antibodies to IL-1 attenuate neuronal loss [36] and in IL-1 deficient mice neuronal loss and infarct volumes are reduced [6]. The early primary source of IL-1 is microglia, but later the cytokine is also produced by astrocytes and expression in oligodendrocytes and neurons has also been detected [59]. There is general consensus that after insults, IL-1 has adverse effects in the brain in vivo, but observations on cultured neurons are less clear.…”

mentioning

confidence: 99%

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Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

189

142

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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Section: The Effect Of the Cytokine On Bdnf Signaling Is Specificmentioning

confidence: 94%

Section: Il-1β; Bdnf; Signal Transduction; Cortical Neuronsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

189

142

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“…Interleukin (IL)-1 is an important pro-inflammatory cytokine which, in addition to actions in peripheral immune and inflammatory processes, is a mediator of diverse forms of neurodegeneration and CNS inflammation (see Rothwell and Luheshi 2000;Allan and Rothwell 2001; for reviews). The IL-1 family comprises three members, the agonists IL-1a and IL-1b, and a naturally occuring receptor antagonist, IL-1ra (Dinarello 1996).…”

mentioning

confidence: 99%

Expression of interleukin‐1 receptors and their role in interleukin‐1 actions in murine microglial cells

Pinteaux

Parker

Rothwell

et al. 2002

Journal of Neurochemistry

154

107

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Interleukin (IL)-1 is an important mediator of acute brain injury and inflammation, and has been implicated in chronic neurodegeneration. The main source of IL-1 in the CNS is microglial cells, which have also been suggested as targets for its action. However, no data exist demonstrating expression of IL-1 receptors [IL-1 type-I receptor (IL-1RI), IL-1 type-II receptor (IL-1RII) and IL-1 receptor accessory protein (IL-1RAcP)] on microglia. In the present study we investigated whether microglia express IL-1 receptors and whether they present target or modulatory properties for IL-1 actions. RT-PCR analysis demonstrated lower expression of IL-1RI and higher expression of IL-1RII mRNAs in mouse microglial cultures compared with mixed glial or pure astrocyte cultures. Bacterial lipopolysaccharide (LPS) caused increased expression of IL-1RI, IL-1RII and IL-1RAcP mRNAs, induced the release of IL-1b, IL-6 and prostaglandin-E 2 (PGE 2 ), and activated nuclear factor jB (NF-jB) and the mitogen-activated protein kinases (MAPKs) p38, and extracellular signal-regulated protein kinase (ERK1/2), but not c-Jun N-terminal kinase (JNK) in microglial cultures. In comparison, IL-1b induced the release of PGE 2 , IL-6 and activated NF-jB, p38, JNK and ERK1/2 in mixed glial cultures, but failed to induce any of these responses in microglial cell cultures. IL-1b also failed to affect LPS-primed microglial cells. Interestingly, a neutralizing antibody to IL-1RII significantly increased the concentration of IL-1b in the medium of LPS-treated microglia and exacerbated the IL-1b-induced IL-6 release in mixed glia, providing the first evidence that microglial IL-1RII regulates IL-1b actions by binding excess levels of this cytokine during brain inflammation. Keywords: interleukin 1 receptors, interleukin 1 signaling, microglial cells, mitogen-activated protein kinase, nuclear factor kappa B.

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Inflammatory Cytokine Gene Polymorphisms and Increased Risk of Parkinson Disease

Wahner¹,

Sinsheimer²,

Bronstein³

et al. 2007

Arch Neurol

132

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Background:The proinflammatory cytokines tumor necrosis factor ␣ (TNF-␣) and IL-1␤ (interleukin 1␤) have a role in neuroinflammation, and functional polymorphisms in the TNF-α and IL-1β genes may affect susceptibility to Parkinson disease (PD).Objective: To investigate whether functional DNA polymorphisms of the TNF-α and IL-1β genes affect the risk of PD.Design: Population-based case-control study.Setting: Three rural California counties (Fresno, Tulare, and Kern).Participants: Two hundred eighty-nine incident idiopathic PD cases and 269 population control subjects, marginally matched by age, sex, and race/ethnicity. Main Outcome Measures:Genotypes of IL-1β-511 and TNF-α-308. Results:We observed a greater than 2-fold increased risk of PD among carriers of the homozygous variant genotype of IL-1β-511 (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.27-4.02) and the homozygous variant genotype of TNF-α-308 (OR, 2.49; 95% CI, 0.90-6.85) and an almost 3-fold increased risk among carriers of the homozygous variant genotype for either or both polymorphisms (OR, 2.92; 95% CI, 1.66-5.16). Conclusions:A smaller magnitude of PD risk increase among carriers of the heterozygous genotype for either or both polymorphisms suggests a gene-dosing effect (OR, 1.45; 95% CI, 0.97-2.16; PϽ.001 for trend). Results were not sensitive to exclusion of all nonwhite subjects or to adjustment for nonsteroidal anti-inflammatory drug use or smoking.

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Interleukin 1 in the brain: biology, pathology and therapeutic target

Cited by 601 publications

References 138 publications

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Expression of interleukin‐1 receptors and their role in interleukin‐1 actions in murine microglial cells

Inflammatory Cytokine Gene Polymorphisms and Increased Risk of Parkinson Disease

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