scholarly journals Sindbis Virus Induces Apoptosis through a Caspase-Dependent, CrmA-Sensitive Pathway

1998 ◽  
Vol 72 (1) ◽  
pp. 452-459 ◽  
Author(s):  
Victor E. Nava ◽  
Antony Rosen ◽  
Michael A. Veliuona ◽  
Rollie J. Clem ◽  
Beth Levine ◽  
...  
Keyword(s):  
Cell Death ◽  
Sindbis Virus ◽  
Cultured Cells ◽  
Cowpox Virus ◽  
Necrosis Factor Alpha ◽  
Viral Proteases ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Cell Suicide

ABSTRACT Sindbis virus infection of cultured cells and of neurons in mouse brains leads to programmed cell death exhibiting the classical characteristics of apoptosis. Although the mechanism by which Sindbis virus activates the cell suicide program is not known, we demonstrate here that Sindbis virus activates caspases, a family of death-inducing proteases, resulting in cleavage of several cellular substrates. To study the role of caspases in virus-induced apoptosis, we determined the effects of specific caspase inhibitors on Sindbis virus-induced cell death. CrmA (a serpin from cowpox virus) and zVAD-FMK (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) inhibited Sindbis virus-induced cell death, suggesting that cellular caspases facilitate apoptosis induced by Sindbis virus. Furthermore, CrmA significantly increased the rate of survival of infected mice. These inhibitors appear to protect cells by inhibiting the cellular death pathway rather than impairing virus replication or by inhibiting the nsP2 and capsid viral proteases. The specificity of CrmA indicates that the Sindbis virus-induced death pathway is similar to that induced by Fas or tumor necrosis factor alpha rather than being like the death pathway induced by DNA damage. Taken together, these data suggest a central role for caspases in Sindbis virus-induced apoptosis.

scholarly journals Tumour Necrosis Factor-Alpha and Nitric Oxide Mediate Apoptosis by D-Galactosamine in a Primary Culture of Rat Hepatocytes: Exacerbation of Cell Death by Cocultured Kupffer Cells

2002 ◽  
Vol 16 (11) ◽  
pp. 791-799 ◽  
Author(s):  
Amira Mohamed Kamal ElSaid Abou-Elella ◽  
Emilio Siendones ◽  
Javier Padillo ◽  
José Luis Montero ◽  
Manuel De la Mata ◽  
...  
Keyword(s):  
Cell Death ◽  
Kupffer Cells ◽  
Inos Expression ◽  
Tnf Alpha ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Inos Inhibition

BACKGROUND: Prostaglandin E1(PGE1) reduces cell death in experimental and clinical liver dysfunction.OBJECTIVES: Whether PGE1protects against d-galactosamine (D-GalN)-associated hepatocyte cell death by the regulation of tumour necrosis factor-alpha (TNF-alpha) and/or nitric oxide (NO) in hepatocytes or cocultured Kupffer cells was examined.METHODS: Anti-TNF-alpha antibodies were used to evaluate the role of TNF-alpha during d-GalN cytotoxicity and its protection by PGE1in cocultured hepatocytes and Kupffer cells. Cell apoptosis and necrosis were assessed by DNA fragmentation and lactate dehydrogenase release, respectively. Nitrite+nitrate (NOx), as NO end products, and TNF-alpha concentrations were measured in the culture medium. The role of NO was determined by measuring inducible NO synthase (iNOS) expression and the effect of its inhibition during d-GalN cytotoxicity and its protection by PGE1.RESULTS: d-GalN enhanced hepatocyte cell death associated with high TNF-alpha and NOx levels in a culture medium. Anti-TNF-alpha and iNOS inhibition suggested that TNF-alpha was mediating apoptosis, but not necrosis, through the stimulation of NO production. The antiapoptotic activity of PGE1was associated with a reduction of NO production, but was blocked by iNOS inhibition. This apparent contradiction was explained by the ability of PGE1to enhance iNOS expression shortly after its administration and inhibit it later during d-GalN treatment. Anti-TNF-alpha antibodies did not reduce the exacerbation ofD-GalN-associated cell death in hepatocytes by cocultured Kupffer cells.CONCLUSION: TNF-alpha mediatesD-GalN-induced apoptosis via NO production in cultured hepatocytes. The protective effect of PGE1againstD-GalN-induced apoptosis is probably through the induction of low iNOS expression that was followed by a reduction of iNOS expression and NO production induced by the hepatotoxin. The exacerbation of hepatocyte cell death by Kupffer cells was not related to TNF-alpha and NO.

The Role of Nuclear Factor-kappaB and Melanogenesis in Tumor Necrosis Factor-Alpha-Induced Apoptosis of Normal Human Melanocytes

2002 ◽  
Vol 15 (5) ◽  
pp. 321-329 ◽  
Author(s):  
Jing Shang ◽  
Jürgen Eberle ◽  
Christoph C. Geilen ◽  
Amir M. Hossini ◽  
Lothar F. Fecker ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Necrosis Factor Alpha ◽  
Human Melanocytes ◽  
Normal Human ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

scholarly journals Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4184-4193 ◽  
Author(s):  
G Eissner ◽  
F Kohlhuber ◽  
M Grell ◽  
M Ueffing ◽  
P Scheurich ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Programmed Cell Death ◽  
Ionizing Radiation ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

In this report, we show that ionizing radiation (IR) at a clinically relevant dose (4 Gy) causes apoptosis in macrovascular and microvascular human endothelial cells. Treatment of irradiated cells with a low dose of bacterial endotoxin (LPS), similar to the levels observed in serum during endotoxemia, enhanced the rate of apoptosis, although LPS alone was unable to induce programmed cell death. The cytokine and endotoxin antagonist interleukin-10 (IL-10) reduced the rate of LPS + IR-induced apoptosis to levels obtained with irradiation alone. Using neutralizing antibodies against tumor necrosis factor- alpha (TNF), we could show crucial involvement of TNF in the LPS- mediated enhancement of IR-induced apoptosis, but not in the IR-induced apoptosis per se. However, further analysis strongly suggested the transmembrane form of TNF (mTNF), but not soluble TNF, to be accountable for the LPS-mediated cytotoxic effects. Studies with anatagonistic receptor specific antibodies clearly showed that TNF receptor type I (TR60) is essential and sufficient to elicit this effect. These findings are of potential clinical importance because they may disclose a relevant mechanism that leads to endothelial damage after radiotherapy or total body irradiation used for conditioning in bone marrow transplantation and that may thus contribute to transplant related complications, especially in association with endotoxemia or related inflammatory states.

scholarly journals The Mitochondrial Permeability Transition Is Required for Tumor Necrosis Factor Alpha-Mediated Apoptosis and Cytochrome c Release

1998 ◽  
Vol 18 (11) ◽  
pp. 6353-6364 ◽  
Author(s):  
Cynthia A. Bradham ◽  
Ting Qian ◽  
Konrad Streetz ◽  
Christian Trautwein ◽  
David A. Brenner ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Necrosis Factor Alpha ◽  
Mitochondrial Permeability ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IκB superrepressor, tumor necrosis factor alpha (TNFα) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFα induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFα treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFα treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFα-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing ΔFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFα, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFα-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.

scholarly journals Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta-converting enzyme-mediated apoptosis.

1996 ◽  
Vol 184 (2) ◽  
pp. 717-724 ◽  
Author(s):  
R M Friedlander ◽  
V Gagliardini ◽  
R J Rotello ◽  
J Yuan
Keyword(s):  
Cell Death ◽  
Neutralizing Antibodies ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Converting Enzyme ◽  
Necrosis Factor Alpha ◽  
Trophic Factor Deprivation ◽  
Cell Death Gene ◽  
Factor Alpha ◽  
Induced Apoptosis

Prointerleukin-1 beta (pro-IL-1 beta) is the only known physiologic substrate of the interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), the founding member of the ICE/ced-3 cell death gene family. Since secreted mature IL-1 beta has been detected after apoptosis, we investigated whether this cytokine, when produced endogenously, plays a role in cell death. We found that hypoxia-induced apoptosis can be inhibited by either the IL-1 receptor antagonist (IL-1Ra) or by neutralizing antibodies to IL-1 or to its type 1 receptor. IL-1Ra also inhibits apoptosis induced by trophic factor deprivation in primary neurons, as well as by tumor necrosis factor alpha in fibroblasts. In addition, during the G1/S phase arrest, mature IL-1 beta induces apoptosis through a pathway independent of CrmA-sensitive gene activity. We also demonstrate that Ice, when expressed in COS cells, requires the coexpression of pro-IL-1 beta for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1 beta has antiapoptotic activity when added exogenously before the onset of hypoxia, which we found is caused in part by its ability to downregulate the IL-1 receptor. Our findings demonstrate that pro-IL-1 beta is a substrate of ICE relevant to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1 beta may function as a positive or negative mediator of cell death.

scholarly journals Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

2006 ◽  
Vol 80 (22) ◽  
pp. 10989-10999 ◽  
Author(s):  
Ching G. Ng ◽  
Diane E. Griffin
Keyword(s):  
Sindbis Virus ◽  
Acid Sphingomyelinase ◽  
Wild Type ◽  
Fatal Disease ◽  
Necrosis Factor Alpha ◽  
Enveloped Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Sindbis virus (SV), an enveloped virus with a single-stranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family. In mice, SV infects neurons and can cause apoptosis of immature neurons. Sphingomyelin (SM) is the most prevalent cellular sphingolipid, is particularly abundant in the nervous systems of mammals, and is required for alphavirus fusion and entry. The level of SM is tightly regulated by sphingomyelinases. A defect in acid sphingomyelinase (ASMase) results in SM storage and subsequent intracellular accumulation of SM. To better understand the role of the SM pathway in SV pathogenesis, we have characterized SV infection of transgenic mice deficient in the ASMase gene. ASMase knockout (ASM-KO) mice were more susceptible to SV infection than wild-type (WT) or heterozygous (Het) animals. Titers of SV were higher in the brains of ASM-KO mice than in the brains of WT mice. More SV RNA was detected by in situ hybridization, more SV protein was detected by immunohistochemistry, and more terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were present in the cortex and hippocampus of ASM-KO mice than in those of WT or Het mice. Interleukin-6 (IL-6), but not IL-1β or tumor necrosis factor alpha, was elevated in infected ASM-KO mice compared to levels in WT or Het mice, but studies with IL-6-KO mice and recombinant SV expressing IL-6 showed no role for IL-6 in fatal disease. Together these data indicate that the increase in susceptibility of ASM-KO mice to SV infection was the result of more-rapid replication and spread of SV in the nervous system and increased neuronal death.

scholarly journals Role of Cytochrome c in Apoptosis: Increased Sensitivity to Tumor Necrosis Factor Alpha Is Associated with Respiratory Defects but Not with Lack of Cytochrome c Release

2007 ◽  
Vol 27 (5) ◽  
pp. 1771-1783 ◽  
Author(s):  
Uma D. Vempati ◽  
Francisca Diaz ◽  
Antoni Barrientos ◽  
Sonoko Narisawa ◽  
Abdul M. Mian ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Oxidative Phosphorylation ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Increased Sensitivity ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Although the role of cytochrome c in apoptosis is well established, details of its participation in signaling pathways in vivo are not completely understood. The knockout for the somatic isoform of cytochrome c caused embryonic lethality in mice, but derived embryonic fibroblasts were shown to be resistant to apoptosis induced by agents known to trigger the intrinsic apoptotic pathway. In contrast, these cells were reported to be hypersensitive to tumor necrosis factor alpha (TNF-α)-induced apoptosis, which signals through the extrinsic pathway. Surprisingly, we found that this cell line (CRL 2613) respired at close to normal levels because of an aberrant activation of a testis isoform of cytochrome c, which, albeit expressed at low levels, was able to replace the somatic isoform for respiration and apoptosis. To produce a bona fide cytochrome c knockout, we developed a mouse knockout for both the testis and somatic isoforms of cytochrome c. The mouse was made viable by the introduction of a ubiquitously expressed cytochrome c transgene flanked by loxP sites. Lung fibroblasts in which the transgene was deleted showed no cytochrome c expression, no respiration, and resistance to agents that activate the intrinsic and to a lesser but significant extent also the extrinsic pathways. Comparison of these cells with lines with a defective oxidative phosphorylation system showed that cells with defective respiration have increased sensitivity to TNF-α-induced apoptosis, but this process was still amplified by cytochrome c. These studies underscore the importance of oxidative phosphorylation and apoptosome function to both the intrinsic and extrinsic apoptotic pathways.

scholarly journals Potential Role of Interleukin-18 in the Immunopathogenesis of AIDS: Involvement in Fratricidal Killing of NK Cells

2009 ◽  
Vol 83 (12) ◽  
pp. 5999-6010 ◽  
Author(s):  
Alexandre Iannello ◽  
Suzanne Samarani ◽  
Olfa Debbeche ◽  
Rasheed Ahmad ◽  
Mohamed-Rachid Boulassel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Nk Cell ◽  
Inverse Correlation ◽  
Interleukin 18 ◽  
Necrosis Factor Alpha ◽  
Immunodeficiency Virus ◽  
Factor Alpha

ABSTRACT We had shown earlier that the concentrations of circulating interleukin-18 (IL-18) are increased significantly in human immunodeficiency virus (HIV)-infected persons compared to HIV-seronegative healthy subjects. In the present study, we investigated the consequences of these elevated levels of IL-18 on natural killer (NK) cells and the immunopathogenesis of AIDS. We show here an inverse correlation between IL-18 concentrations and absolute numbers of various subsets of NK cells in infected persons. Recombinant human IL-18 caused increased death of a human NK cell line, as well as of primary human NK cells in vitro. The IL-18-mediated cell death was dependent upon Fas-FasL interactions and tumor necrosis factor alpha. IL-18 induced the expression of FasL on NK cells, increased the transcription from the human FasL promoter, reduced the expression of Bcl-XL in NK cells, and increased their sensitivity to FasL-mediated cell death. These results suggest that increased IL-18 concentrations present in the circulation of HIV-infected persons contribute to the immunopathogenesis of AIDS by altering NK cell homeostasis.

scholarly journals Expression of Secreted Cytokine and Chemokine Inhibitors by Ectromelia Virus

2000 ◽  
Vol 74 (18) ◽  
pp. 8460-8471 ◽  
Author(s):  
Vincent P. Smith ◽  
Antonio Alcami
Keyword(s):  
Immune Evasion ◽  
Cowpox Virus ◽  
Limited Information ◽  
Ectromelia Virus ◽  
Binding Studies ◽  
Homologous Proteins ◽  
Necrosis Factor Alpha ◽  
Cytokine Inhibitors ◽  
Factor Alpha

ABSTRACT The production of secreted proteins that bind cytokines and block their activity has been well characterized as an immune evasion strategy of the orthopoxviruses vaccinia virus (VV) and cowpox virus (CPV). However, very limited information is available on the expression of similar cytokine inhibitors by ectromelia virus (EV), a virulent natural mouse pathogen that causes mousepox. We have characterized the expression and binding properties of three major secreted immunomodulatory activities in 12 EV strains and isolates. Eleven of the 12 EVs expressed a soluble, secreted 35-kDa viral chemokine binding protein with properties similar to those of homologous proteins from VV and CPV. All of the EVs expressed soluble, secreted receptors that bound to mouse, human, and rat tumor necrosis factor alpha. We also detected the expression of a soluble, secreted interleukin-1β (IL-1β) receptor (vIL-1βR) by all of the EVs. EV differed from VV and CPV in that binding of human 125I-IL-1β to the EV vIL-1βR could not be detected. Nevertheless, the EV vIL-1βR prevented the interaction of human and mouse IL-1β with cellular receptors. There are significant differences in amino acid sequence between the EV vIL-1βR and its VV and CPV homologs which may account for the results of the binding studies. The conservation of these activities in EV suggests evolutionary pressure to maintain them in a natural poxvirus infection. Mousepox represents a useful model for the study of poxvirus pathogenesis and immune evasion. These findings will facilitate future study of the role of EV immunomodulatory factors in the pathogenesis of mousepox.

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