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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus transformed cells are susceptible to lysis by human recombinant tumor necrosis factor (TNF). This susceptibility correlates with the presence of E1a in these cells. A flat revertant cell line which expresses a biologically functional E1a but not the transformed phenotype was nevertheless susceptible to TNF. However, flat revertants retransformed by 5-azacytidine, without concomitant reactivation of E1a, were resistant to TNF-alpha. This result suggests TNF susceptibility is not transformation but E1a dependent. To study the mechanism of cytolysis in these cell lines, we examined the possibility that changes in the transcription of E1a were brought about by TNF, as it was reported in the case of a c-myc transformed cell line. The results showed that TNF did not affect either E1a or c-myc transcription in our cells during the development of the cytotoxic response.
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PMID:Tumor necrosis factor mediated cytolysis requires the adenovirus E1a protein but not the transformed phenotype. 214 Apr 84

Human adenoviruses are providing insights into strategies that viruses may adopt to evade immune surveillance. There are 47 serotypes that form six groups (A to F) with different genetic and biological properties. Adenovirus type 2 (Ad2) and Ad5, two group C types, the most common and best understood in terms of molecular biology, cause respiratory infections in young children and often form persistent infections. Following infection, the linear duplex DNA genome is expressed in two broad phases: "early", when viral proteins function to usurp the cell; and "late", when viral DNA and structural proteins are synthesized and virions are assembled. One of the early transcription units, region E3, encodes two proteins that appear to counteract different branches of the host's anti-viral defenses. A 19,000 Mr protein called gp19K protects cells against cytolysis by adenovirus-specific cytotoxic T lymphocytes (CTL). Gp19K has two properties that are crucial to this function: it is localized in the endoplasmic reticulum, and it binds strongly to class I antigens of the major histocompatibility complex (MHC). The effect of these two properties is to block transport of class I antigens to the cell surface. In order to lyse adenovirus-infected cells, CTL must recognize adenovirus peptide antigens complexed with class I major histocompatability complex antigens displayed on the cell surface. Since gp19K prevents this, it renders the cell effectively invisible to CTL. The second anti-immune E3 protein is a 14,700 Mr protein called 14.7K. The 14.7K protects adenovirus-infected cells against cytolysis by tumor necrosis factor (TNF). TNF is a pleiotropic immunoregulatory protein that has anti-viral properties and is believed to provide a defense against virus infections. The 14.7K presumably counteracts the anti-viral effects of TNF in vivo. The mechanism of action of the 14.7K is unknown. Further studies on gp19K and 14.7K should assist our understanding of the immune system and adenovirus pathogenesis.
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PMID:Adenovirus region E3 proteins that prevent cytolysis by cytotoxic T cells and tumor necrosis factor. 253 58

Adenovirus encodes numerous products that counteract host defenses. A virus-encoded RNA, VA RNA1, prevents interferon-mediated shut-off of protein synthesis. Other protein products inhibit interferon-induced gene transcription, prevent cell killing by cytotoxic T cells or block apoptosis, and three sets of proteins independently block the cytolysis and inflammation induced by tumor necrosis factor. Studies of these factors are providing insights into viral pathogenesis.
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PMID:Adenovirus proteins that subvert host defenses. 753 31

A chimeric protein capable of binding and neutralizing tumor necrosis factor (TNF) and lymphotoxin was expressed in mice transduced with a replication-incompetent adenoviral vector into which a TNF inhibitor gene had been engineered. Within 3 days following the injection of 10(9) infectious particles, the TNF inhibitor concentration exceeded 1 mg/ml of plasma; this level of expression was maintained for at least 4 weeks, and detectable TNF inhibitory activity was measured 6 weeks after injection of the recombinant virus. Introduction of the artificial gene produced a phenotypic effect comparable to homozygous deletion of the 55-kDa TNF receptor, in that animals were rendered highly susceptible to infection by Listeria monocytogenes, whereas control animals receiving a replication-incompetent virus coding for beta-galactosidase were capable of resisting Listeria challenge. Adenovirus-mediated transfer of a gene encoding a TNF inhibitor offers a practical means of imposing effective, long-term blockade of TNF activity in vivo for investigational and therapeutic purposes.
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PMID:Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer. 827 68

Adenovirus type 5 encodes a 14.7-kDa protein that protects infected cells from tumor necrosis factor-induced cytolysis by an unknown mechanism. In this report, we demonstrate that infection of cells with an adenovirus vector expressing Fas ligand induced rapid apoptosis that was blocked by coinfection with a virus expressing 14. 7K. Moreover, AdFasL/G infection resulted in the rapid activation of DEVD-specific caspases, and caspase activation was blocked by coinfection with Ad14.7/G. Cell death induced by the overexpression of Fas ligand, Fas-associated death domain-containing protein (FADD)/MORT1, or FADD-like interleukin-1beta-converting enzyme (FLICE)/caspase-8 in a virus-free system was efficiently blocked by 14.7K expression. Moreover, we demonstrate that 14.7K interacts with FLICE. These results support the idea that FLICE is a cellular target for the 14.7-kDa protein.
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PMID:Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis. 948 17

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by granuloma formation. We recently showed that interferon-gamma (IFN-gamma) is essential for inflammation and granuloma formation in HP. Interleukin-10 (IL-10) counteracts many of the biologic effects of IFN-gamma, suggesting that IL-10 modulates inflammation and granuloma formation in HP. We compared the expression of HP in C57BL/6 mice that lack IL-10 (IL-10 knockout [KO]) with that in wild-type (WT) littermates. IL-10 KO and WT mice were exposed to the thermophilic bacteria Saccharopolyspora rectivirgula or to saline alone for 3 wk. The IL-10 KO mice had higher cell counts in their bronchoalveolar lavage fluid (2.85 +/- 0. 43 x 10(6)) than did WT mice (1.4 +/- 0.3 x 10(6)/ml; P < 0.03), with a more prominent neutrophil response. They also had greater inflammation after antigen exposure than did the WT mice (P < 0. 0001). There was increased upregulation of IFN-gamma, IL-1, and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the lungs of IL-10 KO mice. Adenovirus-mediated gene transfer of IL-10 to the liver of IL-10 KO mice reduced the inflammation from that seen in WT mice. These studies show that IL-10 has important anti-inflammatory properties in HP, and that lack of this cytokine leads to a more severe granulomatous inflammatory response.
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PMID:Interleukin-10 modulates the severity of hypersensitivity pneumonitis in mice. 980 46

Gelsolin, an 80 kDa actin-severing protein, has been recently identified as a substrate for the cell death-promoting cysteinyl protease caspase-3 (CPP32/apopain/YAMA). We investigated the role of gelsolin and its cleavage product in apoptosis of vascular smooth muscle cells (SMC) induced by the proinflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Treatment with a combination of IFN-gamma and TNF-alpha reduced viability of SMC in a time- and concentration-dependent manner. Immunoblotting revealed that SMC treated with the cytokines generated a 41 kDa gelsolin fragment. The gelsolin fragmentation required activation of caspase-3, as the caspase-3 inhibitor diminished cytokine-induced cell death as well as the fragmentation. Gelsolin cleavage was accompanied by a reduction in F-actin content and by a marked disruption of cell structure. Adenovirus-mediated transfection of this N-terminal gelsolin fragment into SMC altered cell morphology, reduced cell viability, increased the number of TUNEL-positive cells, and promoted internucleosomal DNA fragmentation. Compared to wild-type cells, gelsolin-deficient SMC showed resistance to apoptosis induced by the inflammatory cytokines. These results suggest a mechanistic role for gelsolin cleavage during SMC apoptosis, a process implicated in vessel development as well as stability of atherosclerotic plaque.
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PMID:Caspase-3-induced gelsolin fragmentation contributes to actin cytoskeletal collapse, nucleolysis, and apoptosis of vascular smooth muscle cells exposed to proinflammatory cytokines. 993 Jun 54

Adenovirus-mediated gene transfer into the brain is associated with significant inflammation and activation of anti-vector and anti-transgene immune responses that curtail the gene delivery of adenoviruses and therapeutic efficacy. Elucidating the molecular mediators of inflammatory and immune responses to adenoviruses injected into the brain should allow us to inhibit their inflammatory actions, thereby reducing vector clearance and enhance adenoviral-mediated gene transfer into the CNS. Cytokines are primary mediators of the immune response and are released during inflammation. Here we report for the first time that injection of replication-deficient adenovirus vectors into the cerebral ventricles of rats causes a rapid increase in body temperature. This fever response precedes any vector-encoded transgene expression and occurs with vectors encoding no transgene, as well as with vectors encoding a therapeutic transgene i.e., HSV1-thymidine kinase. No fever is detected after infection of the striatum, an important brain target in studies on neurodegeneration. After infection of the brain ventricles, CSF levels of immunoreactive tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta increase significantly (up to 300-fold). In the hypothalamus, the locus of thermoregulation in the brain, only IL-1beta and IL-6 are significantly elevated. A neutralizing TNF-alpha antibody has no effect on adenovirus-induced fever. However, pretreatment with either the IL-1 receptor antagonist or the cyclooxygenase inhibitor flurbiprofen completely abolishes adenovirus-induced fever, suggesting that IL-1 and prostaglandins are direct mediators of this response. These results are the first to demonstrate that IL-1, but not TNF-alpha, is the main mediator of a very early inflammatory response to adenovirus in the brain.
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PMID:Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain. 995 27

Adenovirus E1A DNA and proteins are detected in lung epithelial cells of patients with chronic obstructive pulmonary disease. In investigating E1A regulation of inflammatory mediator expression in human lung epithelial cells, we found increased intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 expression after lipopolysaccharide (LPS) stimulation of A549 cells stably transfected with adenovirus 5 E1A. We now show that E1A-dependent induction of interleukin-8 expression is specific to LPS, superinduced by cycloheximide, and not observed after tumor necrosis factor or phorbol 12-myristate 13-acetate stimulation. Electrophoretic mobility shift assays revealed that tumor necrosis factor or phorbol 12-myristate 13-acetate induced nuclear factor-kappaB binding complexes of Rel A and p50 in E1A and control transfectants, whereas LPS was effective only in E1A transfectants. Similarly, LPS-induced nuclear translocation of nuclear factor-kappaB was observed only in E1A transfectants. CCAAT-enhancer binding protein binding was undetected and activator protein-1 binding was unaffected by LPS in either cell type, whereas basal mRNA levels of c-jun were unchanged by E1A. We conclude that E1A enhances the expression of these inflammatory mediator genes by modulating events specific to LPS-triggered nuclear factor-kappaB induction in these cells.
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PMID:Endotoxin-specific NF-kappaB activation in pulmonary epithelial cells harboring adenovirus E1A. 1048 59

In the presence of a protein synthesis inhibitor, cycloheximide, tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), or lipopolysaccharide (LPS) induces human umbilical vein endothelial cells (HUVECs) to undergo apoptosis, suggesting that constitutive or inducible cytoprotective pathways are required for cell survival. We studied the correlation between nuclear factor-kappaB (NF-kappaB) activation and cell death induced by TNF-alpha, IL-1beta, or LPS. Adenovirus-mediated overexpression of a dominant-negative IkappaBalpha (inhibitor of kappaB) mutant blocked NF-kappaB activation by gel shift assay and blocked induction of vascular cell adhesion molecule-1 protein by TNF-alpha, IL-1beta, and LPS, a NF-kappaB-dependent response. In cells overexpressing the IkappaBalpha mutant, TNF-alpha induced cell death, whereas IL-1beta or LPS did not. We conclude that cell survival following TNF-alpha stimulation is NF-kappaB-dependent but that a constitutive or inducible NF-kappaB-independent pathway(s) protects IL-1beta- or LPS-treated HUVECs from cell death.
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PMID:NF-kappaB activation is required for human endothelial survival during exposure to tumor necrosis factor-alpha but not to interleukin-1beta or lipopolysaccharide. 1049 54


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