NFκB Activation Is Required for the Neuroprotective Effects of Pigment Epithelium-derived Factor (PEDF) on Cerebellar Granule Neurons

Yabe, Takeshi; Wilson, Delores; Schwartz, Joan P.

doi:10.1074/jbc.m107831200

Cited by 127 publications

(90 citation statements)

References 63 publications

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“…Inhibition of NF-kB nuclear translocation by PEDF would thus suppress subsequent NF-kB DNA binding and activation. Interestingly, previous studies showed that activation of NF-kB in neurons is responsible for the neuroprotective activity of PEDF (Yabe et al 2001). In our present study, we did not observe a protective effect of PEDF on HOG-LDL-induced apoptosis of pericytes nor activation of NF-kB by PEDF (data not shown), suggesting that the effect of PEDF on NF-kB activation is cell-type specific.…”

Section: Discussioncontrasting

confidence: 45%

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Zhang¹,

Wang²,

Dashti³

et al. 2008

Journal of Molecular Endocrinology

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Oxidized and/or glycated low-density lipoprotein (LDL) may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 mg/ml native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor-kB (NF-kB) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO K ) formation, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-kB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kB activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO K formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of superoxide dismutase 1 expression. Taken together, these results demonstrate proinflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.

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Section: Discussioncontrasting

confidence: 45%

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Zhang¹,

Wang²,

Dashti³

et al. 2008

Journal of Molecular Endocrinology

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“…A differential role of TNFR1 and TNFR2 has also been reported for hippocampal neurons responding to TNF alone with TNFR1 inducing both NF-B activation and cell death, whereas TNFR2 was found to stimulate p38 mitogen-activated protein kinase (11). However, this study neither addressed the functional significance of TNFR2-mediated p38 activation nor resolved the underlying mechanism of apoptosis dominance in these cells in the presence of an apparently strong NF-B activation (11), which is considered to play an important role in neuroprotection (34). As an example, the (35,36).…”

Section: Tnfr1contrasting

confidence: 41%

Tumor Necrosis Factor (TNF)-mediated Neuroprotection against Glutamate-induced Excitotoxicity Is Enhanced by N-Methyl-D-aspartate Receptor Activation

Marchetti

Klein

Schlett

et al. 2004

Journal of Biological Chemistry

387

339

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We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamateinduced excitotoxicity in primary cortical neurons. TNFexpressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1 ؊/؊ mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2 ؊/؊ neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-B (NF-B) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-B pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-B activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-B activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-Daspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-B activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-B activity was essential for neuronal survival. Thus, the duration of NF-B activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs. Tumor necrosis factor (TNF)1 is a prominent proinflammatory mediator that has been causally associated with the pathophysiology of several acute and chronic diseases, in particular rheumatoid arthritis and Morbus Crohn (1, 2). Up-regulated TNF expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF in these diseases as well (3-7). The membrane-expressed form of TNF signals through both TNF receptors (TNFR1 and TNFR2), whereas soluble TNF proteolytically cleaved from the membrane form acts mainly via TNFR1 (8). Signal pathways initiated from the death domain-containing TNFR1, leading to both proapoptotic and antiapoptotic cellular responses, have been studied in great detail (9). In contrast, there is less information regarding the molecular mechanisms surrounding signal pathways and cellular responses solely initiated via TNFR2 because of concomitant TNFR1 signals in normal situations. The evaluation of the physiological role of TNFR2 by large depends on data obtained from TNFR1 Ϫ/Ϫ mice. We have recently investigated the role of TNF and its receptors in retinal ischemia and unraveled an antagonistic function of TNFR1 and TNFR2. TNFR2 exerts neuroprotection in a phosphatidylinositol 3-kinase (PI3K) dependent manner, which is counterbalanced by the neurodegenerative action of TNFR1 (10). TNFR1 h...

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“…One potential mediator of MEK-ERK-independent B-Raf signaling is NF-jB. Several studies performed in a variety of in vivo and in vitro paradigms have shown the importance of NF-jB for neuronal survival (Yu et al 1999;Glazner et al 2000;Koulich et al 2001;Yabe et al 2001;Bhakar et al 2002;reviewed in Mattson et al 2000). The ability of c-Raf to signal via NF-jB in a MEK-ERK independent manner has been documented (Baumann et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of NF-jB protects neurons against a variety of apoptotic stimuli and reduced NF-jB activity has been associated with neurodegeneration both in vitro and in vivo survival (Yu et al 1999;Glazner et al 2000;Koulich et al 2001;Yabe et al 2001;Bhakar et al 2002;reviewed in Mattson et al 2000). Although the precise mechanism has not been elucidated, c-Raf is known to activate NF-jB in non-neuronal cells via a MEK-ERKindependent mechanism (Foo and Nolan 1999;Pearson et al 2000).…”

Section: Gw5074 Delays Down-regulation Of Akt Activity But Inhibits Amentioning

confidence: 99%

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

Chin

Liu

Morrison

et al. 2004

Journal of Neurochemistry

111

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Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 {5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone}, a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-jB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-jB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

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NFκB Activation Is Required for the Neuroprotective Effects of Pigment Epithelium-derived Factor (PEDF) on Cerebellar Granule Neurons

Cited by 127 publications

References 63 publications

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Tumor Necrosis Factor (TNF)-mediated Neuroprotection against Glutamate-induced Excitotoxicity Is Enhanced by N-Methyl-D-aspartate Receptor Activation

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

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