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 Induction of Interleukin-4 (IL-4) by Legionella pneumophila Infection in BALB/c Mice and Regulation of Tumor Necrosis Factor Alpha, IL-6, and IL-1β

2000 ◽  
Vol 68 (9) ◽  
pp. 5234-5240 ◽  
Author(s):  
Catherine Newton ◽  
Shannon McHugh ◽  
Ray Widen ◽  
Noriya Nakachi ◽  
Thomas Klein ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Legionella Pneumophila ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT Infection of BALB/c mice with a sublethal concentration ofLegionella pneumophila causes an acute disease that is resolved by innate immune responses. The infection also initiates the development of adaptive Th1 responses that protect the mice from challenge infections. To study the early responses, cytokines induced during the first 24 h after infection were examined. In the serum, interleukin-12 (IL-12) was detectable by 3 h and peaked at 10 h, while gamma interferon was discernible by 5 h and peaked at 8 h. Similar patterns were observed in ex vivo cultures of splenocytes. A transient IL-4 response was also detected by 3 h postinfection in ex vivo cultures. BALB/c IL-4-deficient mice were more susceptible to L. pneumophila infection than were wild-type mice. The infection induced higher serum levels of acute-phase cytokines (tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6), and reducing TNF-α levels with antibodies protected the mice from death. Moreover, the addition of IL-4 to L. pneumophila-infected macrophage cultures suppressed the production of these cytokines. Thus, the lack of IL-4 in the deficient mice resulted in unchecked TNF-α production, which appeared to cause the mortality. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is induced by IL-4 during Listeria monocytogenesinfection, was detected at between 2 and 30 h after infection. However, MCP-1 did not appear to be induced by IL-4 or to be required for the TNF-α regulation by IL-4. The data suggest that the early increase in IL-4 serves to regulate the mobilization of acute phase cytokines and thus controls the potential harmful effects of these cytokines.

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 Endogenous Interleukin-6 Plays a Crucial Protective Role in Streptococcal Toxic Shock Syndrome via Suppression of Tumor Necrosis Factor Alpha Production

2005 ◽  
Vol 73 (6) ◽  
pp. 3745-3748 ◽  
Author(s):  
Hongyan Diao ◽  
Masashi Kohanawa
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Protective Role ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT During a Streptococcus pyogenes infection in interleukin-6 (IL-6)-deficient mice, there is elevation of serum tumor necrosis factor alpha (TNF-α) levels, muscular necrosis, and death compared with infection of C57BL/6 mice. Anti-TNF-α monoclonal antibody treatment decreased mortality and muscular necrosis in the infected IL-6-deficient mice. These results suggest that IL-6 plays a crucial protective role via suppression of TNF-α production in S. pyogenes infection.

scholarly journals Destructive Arthritis in Vaccinated Interferon Gamma-Deficient Mice Challenged with Borrelia burgdorferi: Modulation by Tumor Necrosis Factor Alpha

2003 ◽  
Vol 10 (1) ◽  
pp. 44-52 ◽  
Author(s):  
John A. Christopherson ◽  
Erik L. Munson ◽  
Douglas M. England ◽  
Cindy L. Croke ◽  
Monica C. Remington ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Borrelia Burgdorferi ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT We found that Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-γ0) mice challenged with B. burgdorferi developed prominent chronic destructive osteoarthropathy. When these mice were treated with anti-tumor necrosis factor alpha (TNF-α) antibody, the severity of the destructive osteoarthritis was enhanced and affected the mobility of the animals. In addition, extensive swelling of the hind paws occurred. In contrast, treatment of B. burgdorferi-vaccinated, challenged IFN-γ0 mice with recombinant TNF-α (rTNF-α) inhibited the development of arthritis, including swelling of the hind paws. Moreover, treatment of vaccinated, challenged IFN-γ0 mice with anti-TNF-α inhibited fourfold the production of an antibody that kills B. burgdorferi, while treatment of vaccinated, challenged IFN-γ0 mice with rTNF-α slightly elevated the level of the borreliacidal antibody. These results suggest that the level of TNF-α directly or indirectly regulates the production of borreliacidal antibody and the development of vaccine-induced destructive Lyme osteoarthritis. Studies are in progress to determine the mechanism by which TNF-α-dependent cytokines generate the destructive arthritis.

scholarly journals Heat Shock Factor 1 Protects Mice from Rapid Death duringListeria monocytogenesInfection by Regulating Expression of Tumor Necrosis Factor Alpha during Fever

2010 ◽  
Vol 79 (1) ◽  
pp. 177-184 ◽  
Author(s):  
Patience Murapa ◽  
Martin R. Ward ◽  
Siva K. Gandhapudi ◽  
Jerold G. Woodward ◽  
Sarah E. F. D'Orazio
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Heat Shock Factor 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACTHeat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42°C). However, we recently showed that HSF1 is activated at a lower temperature (39.5°C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance ofListeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8+T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2°C inL. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than didHSF1+/+littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1-deficient mice did not show a defect in CD8+T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses ofL. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-α enhanced the survival of HSF1-deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens.

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 Critical Role of the Complement System in Group B Streptococcus-Induced Tumor Necrosis Factor Alpha Release

2003 ◽  
Vol 71 (11) ◽  
pp. 6344-6353 ◽  
Author(s):  
Ofer Levy ◽  
Rochelle M. Jean-Jacques ◽  
Colette Cywes ◽  
Richard B. Sisson ◽  
Kol A. Zarember ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Alternative Pathway ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Group B ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-α), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-α release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-α release, and there are conflicting reports as to the host receptors involved. In a human whole-blood assay system, GBS type III COH-1 potently induced substantial monocyte TNF-α release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-α release in newborn cord blood. Remarkably, GBS-induced TNF-α release from human monocytes was enhanced ∼1,000-fold by heat-labile serum components. Experiments employing C2-, C3-, or C7-depleted serum demonstrated that C3 activation via the alternative pathway is crucial for potent GBS-induced TNF-α release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-α release. Preincubation with human serum enhanced the TNF-α-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-α release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin β subunit CD18 and the α subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-α response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-α release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation.

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.

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