Tumor Necrosis Factor: An Apoptosis JuNKie?

Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell (Impact Factor: 32.24). 03/2004; 116(4):491-7.
Source: PubMed


TNF's main function is to stimulate inflammation by turning on gene transcription through the IKK/NFkappaB and JNK/AP-1 signaling cascades. TNF also can trigger apoptosis through caspase-8, but the role and underlying mechanism of this activity are not fully understood. Here, we review recent data on the role of JNK in the regulation of TNF-dependent apoptosis and discuss what is known so far about how cells decide whether to live or die in response to TNF.

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Available from: Avi Ashkenazi, Oct 09, 2015
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    • "TNF is a key inducer of proinflammatory genes. A large body of evidence shows that TNF-␣ signaling is involved in apoptosis mediated by TNF receptors [39] [40], the c-Jun N-terminal kinase (JNK) cascade [41] [42] [43], and ROS accumulation [33] [44] [45]. NF-κB plays an anti-apoptotic role against TNF induced apoptosis during inflammation by inhibiting ROS accumulation, suppressing JNK signaling, and inducing a number of genes that inhibit apoptosis, including the cellular inhibitors of apoptosis, caspase-8-c-FLIP (FLICE inhibitory protein), and Bcl-2 [46]. "
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    ABSTRACT: Studies have shown an increased expression of mitochondrial ferritin (FtMt) and an antioxidant role for the protein in the brains of Alzheimer's disease (AD) patients. However, little information is available concerning the role of FtMt in other AD pathologies, including inflammation and amyloidogenesis. Therefore, we investigated the regulation and function of FtMt in inflammation and amyloidogenesis. FtMt protein expression was increased by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), whereas FtMt mRNA levels were increased by TNF-α but not by IL-1β or IL-6 in IMR-32 cells. The transcription factor nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, suppressed this TNF-α-induced FtMt expression. FtMt overexpression increased NF-κB activity and translocation of p65 into the nucleus in HEK293 cells. Conversely, knockdown of FtMt attenuated TNF-α-induced NF-κB activity. Overexpression of FtMt inhibited TNF-α-induced apoptosis in the cell culture. FtMt overexpression reduced iron-mediated expression of amyloid-β protein precursor and decreased NF-κB-dependent increases in β- and γ-secretase, leading to decreased amyloid-β production. Our data provide new insights into the mechanism underlying the regulation of FtMt expression by proinflammatory cytokines and indicate further roles for FtMt in AD.
    Journal of Alzheimer's disease: JAD 01/2015; 45(3). DOI:10.3233/JAD-142595 · 4.15 Impact Factor
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    • "Tumor necrosis factor-α is a pleiotropic cytokine that, depending on the cellular context, can regulate a number of cellular functions, including inflammation, proliferation, differentiation, and cell death or survival (Parameswaran and Patial, 2010; Varfolomeev and Ashkenazi, 2004). The major producers of TNF-α are macrophages, important players in the innate immune response (Parameswaran and Patial, 2010). "
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    ABSTRACT: Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion. © 2014 The Authors. Phytotherapy Research published by John Wiley & Sons, Ltd.
    Phytotherapy Research 10/2014; 29(2). DOI:10.1002/ptr.5253 · 2.66 Impact Factor
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    • "TNF-a is a multifunctional cytokine that regulates the immune– inflammatory reaction, and the survival and death of various cells [6] [7]. Errors in TNF-a production have been considered to be key in the pathogenesis of a number of diseases, including infectious, autoimmune, endocrine and neoplastic diseases [8] [9]. "
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    ABSTRACT: Objective: Tumor necrosis factor-alpha (TNF-α) has been found to be associated with gastric carcinogenesis, but individually published results have been inconclusive. The aim of this study was to explore the relationship between the TNF-α-308 G/A polymorphism and gastric cancer risk. Methods: MEDLINE, EMBASE and the COCHRANE library databases were searched for relevant articles to identify all available data. The odds ratios (ORs) with 95% confidence intervals (95% CIs) from each study were used to assess the association between the TNF-α-308 G/A polymorphism and gastric cancer risk. Results: This meta-analysis included 30 studies (32 datasets) involving 7009 gastric cancer cases and 12,119 control subjects. Overall, a significant association was found between the TNF-α-308 G/A polymorphism and gastric cancer in AA+GA vs. GG (dominant contrast model) (OR=1.20, 95% CI=1.07-1.34, p=0.001). With stratification based on ethnicity, the TNF-α-308 G/A polymorphism was correlated with gastric cancer risk in Caucasians, using the dominant contrast model (OR=0.74, 95% CI=0.57-0.96, p=0.02), but not in East Asians and other ethnic groups. In the comprehensive subgroup analysis, a significant association was also found in recent articles (published after 2005), population-based high-quality studies, hospital-based high-quality studies, studies using the TaqMan method and non-cardia subgroups. However, the TNF-α-308 G/A polymorphism was not associated with specific histological types of gastric cancer risk. Conclusions: The TNF-α-308 G/A polymorphism may contribute to susceptibility to gastric cancer in Caucasians, especially for non-cardia gastric cancer, as most strongly demonstrated in high-quality studies and in studies using the TaqMan genotyping method. Furthermore, we recommend the TaqMan method as the preferred genotyping method in DNA polymorphism studies.
    Cytokine 08/2014; 70(2). DOI:10.1016/j.cyto.2014.07.005 · 2.66 Impact Factor
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