scholarly journals The MC160 Protein Expressed by the Dermatotropic Poxvirus Molluscum Contagiosum Virus Prevents Tumor Necrosis Factor Alpha-Induced NF-κB Activation via Inhibition of I Kappa Kinase Complex Formation

2006 ◽  
Vol 80 (2) ◽  
pp. 578-586 ◽  
Author(s):  
Daniel Brian Nichols ◽  
Joanna L. Shisler
Keyword(s):  
Signal Transduction ◽  
Complex Formation ◽  
Tumor Necrosis ◽  
Molluscum Contagiosum ◽  
Tnf Receptor ◽  
Molluscum Contagiosum Virus ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The pluripotent cytokine tumor necrosis factor alpha (TNF-α) binds to its cognate TNF receptor I (TNF-RI) to stimulate inflammation via activation of the NF-κB transcription factor. To prevent the detrimental effects of TNF-α in keratinocytes infected with the molluscum contagiosum virus (MCV), this poxvirus is expected to produce proteins that block at least one step of the TNF-RI signal transduction pathway. One such product, the MC160 protein, is predicted to interfere with this cellular response because of its homology to other proteins that regulate TNF-RI-mediated signaling. We report here that expression of MC160 molecules did significantly reduce TNF-α-mediated NF-κB activation in 293T cells, as measured by gene reporter and gel mobility shift assays. Since we observed that MC160 decreased other NF-κB activation pathways, namely those activated by receptor-interacting protein, TNF receptor-associated factor 2, NF-κB-inducing kinase, or MyD88, we hypothesized that the MC160 product interfered with I kappa kinase (IKK) activation, an event common to multiple signal transduction pathways. Indeed, MC160 protein expression was associated with a reduction in in vitro IKK kinase activity and IKK subunit phosphorylation. Further, IKK1-IKK2 interactions were not detected in MC160-expressing cells, under conditions demonstrated to induce IKK complex formation, but interactions between the MC160 protein and the major IKK subunits were undetectable. Surprisingly, MC160 expression correlated with a decrease in IKK1, but not IKK2 levels, suggesting a mechanism for MC160 disruption of IKK1-IKK2 interactions. MCV has probably retained its MC160 gene to inhibit NF-κB activation by interfering with signaling via multiple biological mediators. In the context of an MCV infection in vivo, MC160 protein expression may dampen the cellular production of proinflammatory molecules and enhance persistent infections in host keratinocytes.

scholarly journals Effect of Deficiency of Tumor Necrosis Factor Alpha or Both of Its Receptors on Streptococcus pneumoniae Central Nervous System Infection and Peritonitis

2001 ◽  
Vol 69 (11) ◽  
pp. 6881-6886 ◽  
Author(s):  
Andreas Wellmer ◽  
Joachim Gerber ◽  
Jasmin Ragheb ◽  
Gregor Zysk ◽  
Tammo Kunst ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Tumor Necrosis ◽  
Neuronal Damage ◽  
Central Nervous System Infection ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) and TNF-β are key mediators in bacterial inflammation. We therefore examined the role of TNF-α and its two receptors in murine pneumococcal central nervous system infection. TNF-α knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-α-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-α deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-α or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 102 CFU of S. pneumoniaeproduced fatal peritonitis in TNF-α-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-α-deficient mice. The lack of TNF-α or its receptors renders mice more susceptible to S. pneumoniae infections.

scholarly journals Candida albicans-Derived β-1,2-Linked Mannooligosaccharides Induce Desensitization of Macrophages

2000 ◽  
Vol 68 (2) ◽  
pp. 965-968 ◽  
Author(s):  
Thierry Jouault ◽  
Chantal Fradin ◽  
Pierre-André Trinel ◽  
Daniel Poulain
Keyword(s):  
Signal Transduction ◽  
Candida Albicans ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
No Release ◽  
Factor Alpha ◽  
Culture Supernatants ◽  
Arachidonic Acid Derivatives ◽  
Necrosis Factor

ABSTRACT Candida albicans β-1,2-oligomannosides stimulate macrophage tumor necrosis factor alpha (TNF-α) but not NO release. This stimulation desensitized macrophages by altering β-1,2-oligomannoside-dependent TNF-α production and lipopolysaccharide-dependent TNF-α and NO secretion. Desensitization was not related to tyrosine phosphorylation signal transduction but was transferred by culture supernatants in which arachidonic acid derivatives were evidenced.

scholarly journals Roles of Tumor Necrosis Factor Alpha (TNF-α) and the p55 TNF Receptor in CD1d Induction and Coxsackievirus B3-Induced Myocarditis

2005 ◽  
Vol 79 (5) ◽  
pp. 2659-2665 ◽  
Author(s):  
S. A. Huber ◽  
D. Sartini
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Coxsackievirus B3 ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Giving C57BL/6 mice 104 PFU of coxsackievirus B3 (H3 variant) fails to induce myocarditis, but increasing the initial virus inoculum to 105 or 106 PFU causes significant cardiac disease. Virus titers in the heart were equivalent at days 3 and 7 in mice given all three virus doses, but day 3 titers in the pancreases of mice inoculated with 104 PFU were reduced. Tumor necrosis factor alpha (TNF-α) concentrations in the heart were increased in all infected mice, but cytokine levels were highest in mice given the larger virus inocula. TNF-α−/− and p55 TNF receptor-negative (TNFR−/−) mice developed minimal myocarditis compared to B6;129 or C57BL/6 control mice. p75 TNFR−/− mice were as disease susceptible as C57BL/6 animals. No significant differences in virus titers in heart or pancreas were observed between the groups, but C57BL/6 and p75 TNFR−/− animals showed 10-fold more inflammatory cells in the heart than p55 TNFR−/− mice, and the cell population was comprised of high concentrations of CD4+ gamma interferon-positive and Vγ4+ cells. Cardiac endothelial cells isolated from C57BL/6 and p75 TNFR−/− mice upregulate CD1d, the molecule recognized by Vγ4+ cells, but infection of TNF−/− or p55 TNFR−/− endothelial cells failed to upregulate CD1d. Infection of C57BL/6 endothelial cells with a nonmyocarditic coxsackievirus B3 variant, H310A1, which is a poor inducer of TNF-α, failed to elicit CD1d expression, but TNF-α treatment of H310A1-infected endothelial cells increased CD1d levels to those seen in H3-infected cells. TNF-α treatment of uninfected endothelial cells had only a modest effect on CD1d expression, suggesting that optimal CD1d upregulation requires both infection and TNF-α signaling.

scholarly journals Tumor Necrosis Factor Alpha Enhances Actinobacillus actinomycetemcomitans Leukotoxin-Induced HL-60 Cell Apoptosis by Stimulating Lymphocyte Function-Associated Antigen 1 Expression†

2004 ◽  
Vol 72 (1) ◽  
pp. 269-276 ◽  
Author(s):  
Noboru Yamaguchi ◽  
Chie Kubo ◽  
Yoshikazu Masuhiro ◽  
Edward T. Lally ◽  
Toshihiko Koga ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Actinobacillus Actinomycetemcomitans ◽  
Lymphocyte Function ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT We demonstrated previously that Actinobacillus actinomycetemcomitans leukotoxin (Ltx) is greatly able to induce apoptotic signaling in cells that are positive for lymphocyte function-associated antigen 1 (LFA-1), a cell receptor of Ltx. We investigated in this study whether inflammatory cytokines can regulate apoptosis of human leukemic HL-60 cells induced by Ltx. Of the cytokines tested, tumor necrosis factor alpha (TNF-α) significantly enhanced the Ltx-induced cell apoptosis. Northern and Western blotting analyses showed that TNF-α enhanced the expression of CD11a in the cells at both the mRNA and protein levels but did not do so for CD18 expression. TNF-α also enhanced the binding of Ltx to the cells. We also observed by measuring the mitochondrial transmembrane potential and the generation of superoxide anion that the cytokine enhanced Ltx-induced apoptosis in HL-60 cells. In addition, interleukin-1β significantly enhanced Ltx-induced cell apoptosis, although the enhancing activity was lower than that of TNF-α. These stimulatory effects of both cytokines were also observed for human polymorphonuclear leukocytes. The ability of TNF-α to increase cell susceptibility to Ltx could be inhibited by preincubation of the cells with a monoclonal antibody against TNF receptor 1 but not by preincubation of the cells with a monoclonal antibody against anti-TNF receptor 2. Furthermore, the results of an assay of caspase 3 intracellular activity (PhiPhiLuxG1D2) showed that Ltx-induced caspase 3 activation was completely neutralized by CD18 antibody treatment, although significant neutralization was also observed with anti-CD11a antibody. Taken together, the results of the present study indicate that TNF-α acts as a potent stimulator of Ltx-induced HL-60 cell apoptosis via TNF receptor 1-mediated upregulation of LFA-1 expression.

scholarly journals Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Production by Human Monocytes Involves the Raf-1/MEK1-MEK2/ERK1-ERK2 Pathway

1999 ◽  
Vol 67 (8) ◽  
pp. 3824-3829 ◽  
Author(s):  
Tjomme van der Bruggen ◽  
Suzanne Nijenhuis ◽  
Estia van Raaij ◽  
Jan Verhoef ◽  
B. Sweder van Asbeck
Keyword(s):  
Signal Transduction ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Erk2 Activation ◽  
Necrosis Factor

ABSTRACT During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-κB (NF-κB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-α production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-α levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 μM). In addition, PD-098059 also reduced TNF-α mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-α levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 μM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-α by human monocytes stimulated with LPS.

scholarly journals Interaction of an Adenovirus E3 14.7-Kilodalton Protein with a Novel Tumor Necrosis Factor Alpha-Inducible Cellular Protein Containing Leucine Zipper Domains

1998 ◽  
Vol 18 (3) ◽  
pp. 1601-1610 ◽  
Author(s):  
Yongan Li ◽  
Jian Kang ◽  
Marshall S. Horwitz
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Early region 3 (E3) of group C human adenoviruses (Ad) encodes several inhibitors of tumor necrosis factor alpha (TNF-α) cytolysis, including an E3 14.7-kDa protein (E3-14.7K) and a heterodimer containing two polypeptides of 10.4 and 14.5 kDa. To understand the mechanism by which the viral proteins inhibit TNF-α functions, the E3-14.7K protein was used to screen a HeLa cell cDNA library to search for interacting proteins in the yeast two-hybrid system. A novel protein containing multiple leucine zipper domains without any significant homology with any known protein was identified and has been named FIP-2 (for 14.7K-interacting protein). FIP-2 interacted with E3-14.7K both in vitro and in vivo. It colocalized with Ad E3-14.7K in the cytoplasm, especially near the nuclear membrane, and caused redistribution of the viral protein. FIP-2 by itself does not cause cell death; however, it can reverse the protective effect of E3-14.7K on cell killing induced by overexpression of the intracellular domain of the 55-kDa TNF receptor or by RIP, a death protein involved in the TNF-α and Fas apoptosis pathways. Deletion analysis indicates that the reversal effect of FIP-2 depends on its interaction with E3-14.7K. Three major mRNA forms of FIP-2 have been detected in multiple human tissues, and expression of the transcripts was induced by TNF-α treatment in a time-dependent manner in two different cell lines. FIP-2 has consensus sequences for several potential posttranslational modifications. These data suggest that FIP-2 is one of the cellular targets for Ad E3-14.7K and that its mechanism of affecting cell death involves the TNF receptor, RIP, or a downstream molecule affected by either of these two molecules.

scholarly journals Human Cytomegalovirus Blocks Tumor Necrosis Factor Alpha- and Interleukin-1β-Mediated NF-κB Signaling

2006 ◽  
Vol 80 (23) ◽  
pp. 11686-11698 ◽  
Author(s):  
Christina Montag ◽  
Jutta Wagner ◽  
Iris Gruska ◽  
Christian Hagemeier
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Human Cytomegalovirus ◽  
Tumor Necrosis ◽  
Antiviral Defense ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT NF-κB plays an important role in the early cellular response to pathogens by activating genes involved in inflammation, immune response, and cell proliferation and survival. NF-κB is also utilized by many viral pathogens, like human cytomegalovirus (HCMV), to activate their own gene expression programs, reflecting intricate roles for NF-κB in both antiviral defense mechanisms and viral physiology. Here we show that the NF-κB signaling pathway stimulated by proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) becomes inhibited in HCMV-infected cells. The block to NF-κB signaling is first noticeable during the early phase of infection but is fully established only at later times. Biochemical and genetic evidence demonstrates that the viral inhibition of proinflammatory signaling by distinct cytokines occurs upstream of the convergence point of NF-κB-activating pathways, i.e., the IκB kinase complex, and that it is mediated via different mechanisms. Consistent with this, we further show that an HCMV variant that has lost the ability to downregulate TNF-α-induced NF-κB signaling also fails to downregulate surface expression of TNF receptor 1, thereby mechanistically linking the inhibition of TNF-α-induced NF-κB signaling by HCMV to TNF receptor targeting. Our data support a model whereby HCMV inhibits cytokine-induced NF-κB signaling at later times during infection, and we suggest that this contributes to the inhibition of the cell's antiviral defense program.

scholarly journals Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy: a systematic review and updated meta-analysis.

2020 ◽  
Author(s):  
Wenna Gao ◽  
Ruilin Zhu ◽  
liu yang
Keyword(s):  
Diabetic Retinopathy ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Meta Analysis ◽  
Entire Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

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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