Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

Liu, Shan; Wang, Xing; Li, Yun; Xu, Lei; Yu, Xiaoliang; Ge, Lin; Li, Jun; Zhu, Yanbing; He, Sudan

doi:10.1155/2014/290182

Cited by 62 publications

(63 citation statements)

References 33 publications

(48 reference statements)

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“…TNF-α is a key proinflammatory cytokine regulating inflammation and plays roles in both homeostasis and disease pathophysiology [26]. NF-κB plays an important role in inflammatory processes and is closely related to the expressions of COX-2, iNOS, and TNF-α [27,28].…”

Section: Discussionmentioning

confidence: 99%

Effects of Molybdenum or/and Cadmium on mRNA Expression Levels of Inflammatory Cytokines and HSPs in Duck Spleens

Zhang

Xia

Xiong

et al. 2015

Biol Trace Elem Res

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Cadmium (Cd) and high dietary intake of molybdenum (Mo) can cause multiple-organ injury in animals, but the co-induced toxicity of Mo and Cd to spleen in ducks is not well understood. The aim of this study was to investigate the co-induced effects of Mo and Cd on the mRNA expression levels of inflammatory cytokines and heat shock proteins (HSPs) in duck spleens. Two hundred forty healthy 11-day-old ducks were randomly divided into six groups and treated with a commercial diet containing Mo or/and Cd. After being treated with Mo or/and Cd for 30, 60, 90, and 120 days, the mRNA expression levels of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), HSP60, HSP70, and HSP90 were examined in duck spleens. Histopathology was examined in duck spleens at 120 days. The results indicated that the mRNA expression levels of HSPs were significantly upregulated in the co-induced groups (P < 0.01), while these decreased in the high dietary intake of Mo combined with Cd group at 120 days. Exposure to Mo or/and Cd upregulated the mRNA expression levels of NF-κB, COX-2, and TNF-α in the combination groups (P < 0.01). Furthermore, severe congestion, bleeding, splenic corpuscle structure fuzzy, wall thickness of sheath artery thickening, and oxyhematin were observed in the spleens of combination groups. Meanwhile, the organizational structure damage of the combined groups was more severe than that of the other groups. These results suggested that exposure to Mo or/and Cd might lead to tissue damage, and high expression of HSPs and inflammatory cytokines may play a role in the resistance of spleen toxicity induced by Mo or/and Cd. Interaction of Mo and Cd may have a synergistic effect on spleen toxicity.

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Section: Discussionmentioning

confidence: 99%

Effects of Molybdenum or/and Cadmium on mRNA Expression Levels of Inflammatory Cytokines and HSPs in Duck Spleens

Zhang

Xia

Xiong

et al. 2015

Biol Trace Elem Res

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“…In primary hippocampal neurons, necroptosis was induced via RIP3 upon an ischemic insult [49]. Moreover, it was recently shown in vivo in mice that intracerebroventricular injection with TNF-α caused RIP3-mediated necroptosis of hippocampal neurons [50]. Besides neurons, necroptosis can also occur in activated (by stimulation with different inflammatory stimuli, including TNF-α) primary microglia upon the inhibition of caspase-8 [51].…”

Section: Tnf-α Receptor 1 Signalingmentioning

confidence: 99%

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

et al. 2015

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Numerous studies have revealed the pleiotropic functions of tumor necrosis factor alpha (TNF-α), and have linked it with several neurodegenerative disorders. This review describes the signaling pathways induced by TNF-α via its two receptors (TNFR1 and TNFR2), and their functions in neurodegenerative processes as in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ischemic stroke. It has become clear that TNF-α may exert divergent actions in neurodegenerative disorders, including neurodegenerative and neuroprotective effects, which appear to depend on its signaling via either TNFR1 or TNFR2. Specific targeting of these receptors is a promising therapeutic strategy for many disorders.

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“…Unlike apoptosis, necroptosis does not involve caspase activation. The observation of necroptosis in various neurodegenerative pathologies like hypoxia-ischemia neuronal damage[2], ALS [3],[4], death of hippocampal neurons[5], retinitis pigmentosa[6], age-related macular degeneration[7], among others, makes inhibition of this form of cell death an attractive therapeutic strategy for neurodegenerative diseases[8]. …”

Section: Introductionmentioning

confidence: 99%

ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis

Marcotte

Paramasivam

et al. 2016

PLoS ONE

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MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, a form of programmed cell death. Its phosphorylation by RIPK3 is necessary for triggering necroptosis but not for triggering apoptosis, which makes it a unique target for pharmacological inhibition to block necroptotic cell death. This mechanism has been described as playing a role in disease progression in neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) has been described that reportedly binds to the MLKL pseudokinase domain and prevents necroptosis. Here we describe five compounds that bind to the MLKL ATP-binding site, however the four MLKL-selective compounds have no activity in rescuing cells from necroptosis. We use kinase selectivity panels, crystallography and a new conformationally sensitive method of measuring protein conformational changes (SHG) to confirm that the one previously reported compound that can rescue cells (cpd 1) is a non-selective type II inhibitor that also inhibits the upstream kinase RIPK1. Although this compound can shift the GFE motif of the activation loop to an “out” position, the accessibility of the key residue Ser358 in the MLKL activation loop is not affected by compound binding to the MLKL active site. Our studies indicate that an ATP-pocket inhibitor of the MLKL pseudokinase domain does not have any impact on the necroptosis pathway, which is contrary to a previously reported study.

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Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

Cited by 62 publications

References 33 publications

Effects of Molybdenum or/and Cadmium on mRNA Expression Levels of Inflammatory Cytokines and HSPs in Duck Spleens

Effects of Molybdenum or/and Cadmium on mRNA Expression Levels of Inflammatory Cytokines and HSPs in Duck Spleens

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

ATP-Competitive MLKL Binders Have No Functional Impact on Necroptosis

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