Correlations of Acute Cerebral Hemorrhage Complicated with Stress Ulcer Bleeding with Acute Physiology and Chronic Health Evaluation (APACHE) II Score, Endothelin (ET), Tumor Necrosis Factor-alpha (TNF-α), and Blood Lipids

Background: Mounting evidence has suggested tumor necrosis factor-alpha (TNF-α) can promote the development of diabetic retinopathy (DR), and TNF-α gene variants may influence DR risk. However, the results are quite different. Objectives: To comprehensively address this issue, we performed the meta-analysis to evaluate the association of TNF-α-308 G/A and -238 G/A polymorphism with DR. Method: Data were retrieved in a systematic manner and analyzed using STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Allelic and genotypic comparisons between cases and controls were evaluated. Results: For the TNF-α-308 G/A polymorphism, overall analysis suggested a marginal association with DR [the OR(95%CI) of (GA versus GG), (GA + AA) versus GG, and (A versus G) are 1.21(1.04, 1.41), 1.20(1.03, 1.39), and 1.14(1.01, 1.30), respectively]. And the subgroup analysis indicated an enhanced association among the European population. For the TNF-α-238 G/A polymorphism, there was mild correlation in the entire group [the OR(95%CI) of (GA versus GG) is 1.55(1.14,2.11) ], which was strengthened among the Asian population. Conclusion: The meta-analysis suggested that -308 A and -238 A allele in TNF-α gene potentially increased DR risk and showed a discrepancy in different ethnicities.

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Tumor Necrosis Factor-α Production-Enhancing Properties of Novel Adamantylalkylthio Derivatives of Some Heterocyclic Compounds

Zeitschrift für Naturforschung B ◽

10.1515/znb-2005-0419 ◽

2005 ◽

Vol 60 (4) ◽

pp. 471-475 ◽

Cited By ~ 2

Author(s):

Barbara Orzeszko ◽

Tomasz Świtaj ◽

Anna B. Jakubowska-Mućka ◽

Witold Lasek ◽

Andrzej Orzeszko ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Heterocyclic Compounds ◽

Tumor Necrosis ◽

The Novel ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Factor Α ◽

Derivatives Of ◽

Necrosis Factor

Certain adamantylated heterocycles were previously shown to enhance the secretion of tumor necrosis factor alpha (TNF-α) by murine melanoma cells that have been transduced with the gene for human TNF-α and constitutively expressed this cytokine. The stimulatory potency of those compounds depended, among other factors, on the structure of the linker between the adamantyl residue and the heterocyclic core. In the present study, a series of (1-adamantyl)alkylsulfanyl derivatives of heterocyclic compounds was prepared by alkylation of the corresponding thioheterocyles. Of the novel adamantylalkylthio compounds tested in the aforementioned cell line, 2-(2-adamantan-1-ylethylsulfanyl)- 4-methyl-pyrimidine was found to be the most active

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Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Protein Inhibits Tumor Necrosis Factor Alpha-Induced NF-κB Activation by Interacting with p65/RelA and p50/NF-κB1

Journal of Virology ◽

10.1128/jvi.01952-13 ◽

2013 ◽

Vol 87 (23) ◽

pp. 12935-12948 ◽

Cited By ~ 56

Author(s):

Jie Zhang ◽

Kezhen Wang ◽

Shuai Wang ◽

Chunfu Zheng

Keyword(s):

Tumor Necrosis Factor ◽

Ubiquitin Ligase ◽

Tumor Necrosis ◽

Nuclear Translocation ◽

E3 Ubiquitin Ligase ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor ◽

Hsv 1

NF-κB plays central roles in regulation of diverse biological processes, including innate and adaptive immunity and inflammation. HSV-1 is the archetypal member of the alphaherpesviruses, with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 ICP0 protein, a viral E3 ubiquitin ligase, was shown to significantly suppress tumor necrosis factor alpha (TNF-α)-mediated NF-κB activation. ICP0 was demonstrated to bind to the NF-κB subunits p65 and p50 by coimmunoprecipitation analysis. ICP0 bound to the Rel homology domain (RHD) of p65. Fluorescence microscopy demonstrated that ICP0 abolished nuclear translocation of p65 upon TNF-α stimulation. Also, ICP0 degraded p50 via its E3 ubiquitin ligase activity. The RING finger (RF) domain mutant ICP0 (ICP0-RF) lost its ability to inhibit TNF-α-mediated NF-κB activation and p65 nuclear translocation and degrade p50. Notably, the RF domain of ICP0 was sufficient to interact with p50 and abolish NF-κB reporter gene activity. Here, it is for the first time shown that HSV-1 ICP0 interacts with p65 and p50, degrades p50 through the ubiquitin-proteasome pathway, and prevents NF-κB-dependent gene expression, which may contribute to immune evasion and pathogenesis of HSV-1.

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Analysis of Subcellular RNA Fractions Revealed a Transcription-Independent Effect of Tumor Necrosis Factor Alpha on Splicing, Mediated by Spt5

Molecular and Cellular Biology ◽

10.1128/mcb.01117-15 ◽

2016 ◽

Vol 36 (9) ◽

pp. 1342-1353 ◽

Cited By ~ 10

Author(s):

Gil Diamant ◽

Tal Eisenbaum ◽

Dena Leshkowitz ◽

Rivka Dikstein

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Independent Effect ◽

Necrosis Factor Alpha ◽

Pol Ii ◽

Tnf Α ◽

Factor Alpha ◽

Induced Genes ◽

Necrosis Factor

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) modulates the expression of many genes, primarily through activation of NF-κB. Here, we examined the global effects of the elongation factor Spt5 on nascent and mature mRNAs of TNF-α-induced cells using chromatin and cytosolic subcellular fractions. We identified several classes of TNF-α-induced genes controlled at the level of transcription, splicing, and chromatin retention. Spt5 was found to facilitate splicing and chromatin release in genes displaying high induction rates. Further analysis revealed striking effects of TNF-α on the splicing of 25% of expressed genes; the vast majority were not transcriptionally induced. Splicing enhancement of noninduced genes by TNF-α was transient and independent of NF-κB. Investigating the underlying basis, we found that Spt5 is required for the splicing facilitation of the noninduced genes. In line with this, Spt5 interacts with Sm core protein splicing factors. Furthermore, following TNF-α treatment, levels of RNA polymerase II (Pol II) but not Spt5 are reduced from the splicing-induced genes, suggesting that these genes become enriched with a Pol II-Spt5 form. Our findings revealed the Pol II-Spt5 complex as a highly competent coordinator of cotranscriptional splicing.

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HSP70 Induction by ING Proteins Sensitizes Cells to Tumor Necrosis Factor Alpha Receptor-Mediated Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.01538-06 ◽

2006 ◽

Vol 26 (24) ◽

pp. 9244-9255 ◽

Cited By ~ 43

Author(s):

Xiaolan Feng ◽

Shirin Bonni ◽

Karl Riabowol

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Kinase Inhibitor ◽

Heat Shock Gene ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Primary Fibroblasts ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-α), and p33ING1b protein showed synergy with TNF-α in inducing apoptosis, which correlated with reduced NF-κB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-α-mediated apoptosis by binding I-κΒ kinase gamma and impairing NF-κB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-κB survival pathway important in hypoxia and angiogenesis.

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Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

Journal of Virology ◽

10.1128/jvi.00362-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7790-7798 ◽

Cited By ~ 26

Author(s):

Marlynne Q. Nicol ◽

Jean-Marie Mathys ◽

Albertina Pereira ◽

Kevin Ollington ◽

Michael H. Ieong ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Innate Immune ◽

Hiv Positive ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Immunodeficiency Virus ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

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Transcription Factor AP-2α Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.21.15.4856-4867.2001 ◽

2001 ◽

Vol 21 (15) ◽

pp. 4856-4867 ◽

Cited By ~ 32

Author(s):

Okot Nyormoi ◽

Zhi Wang ◽

Dao Doan ◽

Maribelis Ruiz ◽

David McConkey ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Cells ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Caspase 6 ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACT Several reports have linked activating protein 2α (AP-2α) to apoptosis, leading us to hypothesize that AP-2α is a substrate for caspases. We tested this hypothesis by examining the effects of tumor necrosis factor alpha (TNF-α) on the expression of AP-2 in breast cancer cells. Here, we provide evidence that TNF-α downregulates AP-2α and AP-2γ expression posttranscriptionally during TNF-α-induced apoptosis. Both a general caspase antagonist (zVADfmk) and a caspase 6-preferred antagonist (zVEIDfmk) inhibited TNF-α-induced apoptosis and AP-2α downregulation. In vivo tests showed that AP-2α was cleaved by caspases ahead of the DNA fragmentation phase of apoptosis. Recombinant caspase 6 cleaved AP-2α preferentially, although caspases 1 and 3 also cleaved it, albeit at 50-fold or higher concentrations. Activated caspase 6 was detected in TNF-α-treated cells, thus confirming its involvement in AP-2α cleavage. All three caspases cleaved AP-2α at asp19 of the sequence asp-arg-his-asp (DRHD19). Mutating D19 to A19abrogated AP-2α cleavage by all three caspases. TNF-α-induced cleavage of AP-2α in vivo led to AP-2α degradation and loss of DNA-binding activity, both of which were prevented by pretreatment with zVEIDfmk. AP-2α degradation but not cleavage was inhibited in vivo by PS-431 (a proteasome antagonist), suggesting that AP-2α is degraded subsequent to cleavage by caspase 6 or caspase 6-like enzymes. Cells transfected with green fluorescent protein-tagged mutant AP-2α are resistant to TNF-α-induced apoptosis, further demonstrating the link between caspase-mediated cleavage of AP-2α and apoptosis. This is the first report to demonstrate that degradation of AP-2α is a critical event in TNF-α-induced apoptosis. Since the DRHD sequence in vertebrate AP-2 is widely conserved, its cleavage by caspases may represent an important mechanism for regulating cell survival, proliferation, differentiation, and apoptosis.

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Tumor Necrosis Factor Alpha Inhibits Type I Collagen Synthesis through Repressive CCAAT/Enhancer-Binding Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.20.3.912-918.2000 ◽

2000 ◽

Vol 20 (3) ◽

pp. 912-918 ◽

Cited By ~ 115

Author(s):

Patricia Greenwel ◽

Shizuko Tanaka ◽

Dmitri Penkov ◽

Wen Zhang ◽

Michelle Olive ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Type I Collagen ◽

Type I ◽

Necrosis Factor Alpha ◽

Gene Coding ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor ◽

Stimulation Of

ABSTRACT Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) inhibits ECM accumulation by stimulating the expression of matrix proteolytic enzymes and by downregulating the deposition of structural macromolecules such as type I collagen. Stimulation of ECM degradation has been linked to prolonged activation of jun gene expression by the cytokine. Here we demonstrate that TNF-α inhibits transcription of the gene coding for the α2 chain of type I collagen [α2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a previously identified TNF-α-responsive element. This conclusion was based on the concomitant identification of C/EBPβ and C/EBPδ as TNF-α-induced factors by biochemical purification and expression library screening. It was further supported by the ability of the C/EBP-specific dominant-negative (DN) protein to block TNF-α inhibition of α2(I) collagen but not TNF-α stimulation of the MMP-13 protease. The DN protein also blocked TNF-α downregulation of the gene coding for the α1 chain of type I collagen. The study therefore implicates repressive C/EBPs in the TNF-α-induced signaling pathway that controls ECM formation and remodeling.

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