RETRACTED: A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide

Venters, Homer; Tang, Qingsong; Liu, Qiang; VanHoy, Roger W.; Dantzer, Robert; Kelley, Keith W.

doi:10.1073/pnas.96.17.9879

Cited by 182 publications

(125 citation statements)

References 62 publications

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“…In neurons the wide-ranging nature of regulation at the level of the docking proteins, such as IRS-1, is indicated by the observation that interference at the docking site is not restricted to the effect of IL-1β on neurotrophin signaling in cerebral cortical cells. In an earlier study Venters et al [72] have shown that another proinflammatory cytokine, TNFα interferes with signaling of a member of another trophic factor IGF-1 at the level of IRS-2 in cerebellar granule cells.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism involves a suppression of the activation of the docking proteins [81]. It has also been shown that the IGF-1-promoted survival of cerebellar granule cells is compromised by the proinflammmatory cytokine TNFα by suppressing the activation of the docking protein IGF-2 [72]. Thus like insulin resistance in peripheral tissues and a similar resistance to IGF-1 in cerebellar neurons there may be a mechanism of resistance to neurotrophins in the brain, predisposing neurons to dysfunction and placing them at increased risk for functional defects and degeneration.…”

Section: Discussionmentioning

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

196

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

196

142

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“…Although TNF is unable to induce apoptosis in these cells alone, it is capable of reversing IGF-1 prevention of apoptosis. 277,278 The mechanism for this appears to be via inhibition of IGF-1-receptor-induced phosphorylation of IRS-2 and the subsequent inability of this to activate PI3-kinase. 277,278 These results suggests that with regards to signaling pathways that lead to apoptosis; that inhibition of kinases or activation of phosphatases which signal cell survival may be an important mechanism used by apoptosis inducing signaling pathways.…”

Section: Cross Talk Between Apoptotic and Anti-apoptotic Signaling Pamentioning

confidence: 99%

“…Apoptosis may also occur via the ability of some receptors to inhibit signaling by other receptors that are thought to have a role in prevention of apoptosis. 277,278 These investigators have found using cerebral granular neurons that IGF-1 prevents apoptosis of these cells cultured in low K+ medium. Although TNF is unable to induce apoptosis in these cells alone, it is capable of reversing IGF-1 prevention of apoptosis.…”

Section: Cross Talk Between Apoptotic and Anti-apoptotic Signaling Pamentioning

confidence: 99%

Kinases: positive and negative regulators of apoptosis

2000

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Cells sense and respond to extracellular factors via receptors on the cell surface that trigger intracellular signaling pathways. The signals received by the receptors on hematopoietic cells often determine if the cell proliferates, survives or undergoes apoptosis. Apoptosis can be induced by almost any cytotoxic stimuli. These stimuli may be an absence of signals arising from cellular receptors, stimulation of specific ligand receptors on the cell surface, chemotherapeutic agents, and ionizing radiation or oxygen radicals, as well as a number of other factors. Cellular kinases and phosphatases participate in signaling cascades that influence this process. We review the ability of the calmodulin-dependent-kinases, I-B kinases, PI3-kinases, Jakkinases, PKC, PKA, and MAP kinase signaling pathways (Erk, Jnk, and p38), to influence the apoptotic process. In addition, we discuss the cross-talk that exists between signaling cascades that are pro-apoptotic and anti-apoptotic.

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“…Many of the agents that induce serine/threonine phosphorylation of IRS-1 also activate JNK, including TNF␣, interleukin-1␣, hyperglycemia, and insulin itself (14, 28, 34, 64 -67). Although the phosphorylation of Ser 307 as a general mechanism to inhibit IRS-1 function is not understood, it might provide a framework to understand the inhibition of insulin or IGF-1 signaling by proinflammatory cytokines under a variety of physiological conditions (23,24,28,29,34,68,69).…”

Section: Ser 307 Is Critical For the Inhibition Of Insulin-stimulatedmentioning

confidence: 99%

The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307

Aguirre¹,

Uchida²,

Yenush³

et al. 2000

Journal of Biological Chemistry

1,292

994

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Tumor necrosis factor ␣ (TNF␣) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNF␣ promotes multipotential signal transduction cascades, including the activation of the Jun NH 2 -terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNF␣ on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNF␣ on IRS-1 function.The insulin signaling system is complex, and a common mechanism to explain the occurrence of insulin resistance during diabetes is difficult to resolve. So far, genetic approaches provide important insight into certain early onset forms of diabetes but fail to explain insulin resistance that is associated with common type 2 diabetes (1-4). Recent results support the notion that dysregulation of the insulin receptor and reduced tyrosine phosphorylation of the IRS 1 proteins might contribute significantly to peripheral insulin resistance and ␤-cell failure (5, 6).The principal insulin receptor substrates, IRS-1 and IRS-2, are phosphorylated on multiple tyrosine residues by the activated receptors for insulin, IGF-1, and various other cytokines (7). Tyrosine phosphorylation of IRS-1 and IRS-2 promotes their binding to the Src homology 2 domains in various downstream signaling proteins, including the phosphatidylinositol 3-kinase (PI 3-kinase), Grb-2, SHP2, and others (7,8). During association with IRS proteins, PI 3-kinase is activated, and its phospholipid products promote the recruitment of various serine kinases to the plasma membrane, where they are activated by phosphorylation (9). One of the membrane-associated kinases, protein kinase B/Akt, phosphorylates multiple downstream effectors that promote diverse biological responses, including stimulation of glucose transport, protein and glycogen synthesis, and the regulation of gene expression, which affects cellular proliferation and survival (10, 11).The insulin receptor and the IRS proteins might be counterregulated by degradation, differential expression, or modification by serine/threonine phosphorylation (12-15). Increased serine phosphorylation of IRS-1 is a common finding during insulin resistance and type 2 diabetes (16). However, the mechanism by which serine phosphorylation inhibits insulin signaling is difficult to establish, because IRS-1 contains more than 70 potential serine/threonine residues in consensus sequences for many protein kinases, including casein kinase II, cAMP-dependent protein kinase, prote...

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RETRACTED: A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide

Cited by 182 publications

References 62 publications

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

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

Kinases: positive and negative regulators of apoptosis

The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307

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