Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immature dendritic cells (DCs), unlike mature DCs, require the viral determinant nef to drive immunodeficiency virus (SIV and HIV) replication in coculture with CD4(+) T cells. Since immature DCs may capture and get infected by virus during mucosal transmission, we hypothesized that Nef associated with the virus or produced during early replication might modulate DCs to augment virus dissemination. Adenovirus vectors expressing nef were used to introduce nef into DCs in the absence of other immunodeficiency virus determinants to examine Nef-induced changes that might activate immature DCs to acquire properties of mature DCs and drive virus replication. Nef expression by immature human and macaque DCs triggered IL-6, IL-12, TNF-alpha, CXCL8, CCL3, and CCL4 release, but without up-regulating costimulatory and other molecules characteristic of mature DCs. Coincident with this, nef-expressing immature DCs stimulated stronger autologous CD4(+) T cell responses. Both SIV and HIV nef-expressing DCs complemented defective SIVmac239 delta nef, driving replication in autologous immature DC-T cell cultures. In contrast, if DCs were activated after capturing delta nef, virus growth was not exacerbated. This highlights one way in which nef-defective virus-bearing immature DCs that mature while migrating to draining lymph nodes could induce stronger immune responses in the absence of overwhelming productive infection (unlike nef-containing wild-type virus). Therefore, Nef expressed in immature DCs signals a distinct activation program that promotes virus replication and T cell recruitment but without complete DC maturation, thereby lessening the likelihood that wild-type virus-infected immature DCs would activate virus-specific immunity, but facilitating virus dissemination.
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PMID:Endogenously expressed nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells. 1237 Mar 46

Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin (ADAM) activity. We have previously shown that adenovirally expressed tissue inhibitor of metalloproteinases-3 (TIMP-3) induces apoptosis in melanoma cells and inhibits growth of human melanoma xenografts. Here, we have studied the role of death receptors in apoptosis of melanoma cells induced by TIMP-3. Our results show, that the exposure of three metastatic melanoma cell lines (A2058, SK-Mel-5, and WM-266-4) to recombinant TIMP-3, N-terminal MMP inhibitory domain of TIMP-3, as well as to adenovirally expressed TIMP-3 results in stabilization of tumor necrosis factor receptor-1 (TNF-RI), FAS, and TNF-related apoptosis inducing ligand receptor-1 (TRAIL-RI) on melanoma cell surface and sensitizes these cells to apoptosis induced by TNF-alpha, anti-Fas-antibody and TRAIL. Stabilization of death receptors by TIMP-3 results in activation of caspase-8 and caspase-3, and subsequent apoptosis is blocked by specific caspase-8 inhibitor (Z-IETD-FMK) and by pan-caspase inhibitor (Z-DEVD-FMK). Adenovirus-mediated expression of TIMP-3 in human melanoma xenografts in vivo resulted in increased immunostaining for TNF-RI, FAS, and cleaved caspase-3, and in apoptosis of melanoma cells. Taken together, these results show that TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8.
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PMID:Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. 1268 14

Effects of adenoviral infection on in vivo responses to LPS mediated by TNF-alpha were evaluated in a murine model. Adenovirus-infected mice showed decreased mortality from fulminant hepatitis induced by administration of LPS or staphylococcal enterotoxin B in the presence of D-galactosamine. Importantly, TNF-alpha resistance genes within adenoviral E3 region were not required, because E1,E3-deleted vectors showed similar effects. Adenovirus-infected mice exhibited higher TNF-alpha levels after LPS stimulation, no difference in TNFR1 expression, and similar mortality from Fas-induced fulminant hepatitis. Decreased production of IL-6 and KC in response to exogenous TNF-alpha, in addition to protection from TNF-alpha, suggested that adenoviral infection results in TNF-alpha tolerance.
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PMID:Adenoviral infection decreases mortality from lipopolysaccharide-induced liver failure via induction of TNF-alpha tolerance. 1292 93

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.
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PMID:Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. 1457 80

Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNF-alpha-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-alpha-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (10(5) particles) protects, while high-dose adenovirus (10(10) particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF-alpha dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNF-alpha appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-alpha responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.
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PMID:Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression. 1558 21

Heat shock (HS) treatment has been previously shown to suppress the IkappaB/nuclear factor-kappaB (NF-kappaB) cascade by denaturing, and thus inactivating IkappaB kinase (IKK). HS is characterized by the induction of a group of heat shock proteins (HSPs). However, their role in the HS-induced suppression of the IkappaB/NF-kappaB cascade is unclear. Adenovirus-mediated HSP70 overexpression was found not to suppress the TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway, thus suggesting that HSP70 is unlikely to suppress this pathway. When TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway was regained 24 h after HS, HSP70 was found to be highly up-regulated. Moreover, blocking HSP70 induction delayed TNF-alpha-induced IkappaBalpha degradation and the resolubilization of IKK. In addition, HSP70 associated physically with IKK, suggesting that HSP70 is involved in the recovery process via molecular chaperone effect. Adenovirus-mediated HSP70 overexpression prior to HS blocked the IkappaBalpha stabilizing effect of HS by suppressing IKK insolubilization. Moreover, the up-regulation of endogenous HSP70 by preheating, suppressed this subsequent HS-induced IKK insolubilization, and this effect was abrogated by blocking HSP70 induction. These findings indicate that HSP70 accumulates during HS and negatively regulates the HS-induced suppression of the IkappaB/NF-kappaB cascade by facilitating the renaturation of IKK and blocking its further denaturation.
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PMID:Heat shock protein 70 negatively regulates the heat-shock-induced suppression of the IkappaB/NF-kappaB cascade by facilitating IkappaB kinase renaturation and blocking its further denaturation. 1592 46

TNF-alpha is a major contributor to the pathogenesis of insulin resistance associated with obesity and inflammation by serine phosphorylating and degrading insulin receptor substrate-1. Presently, we further found that pretreatment with TNF-alpha inhibited insulin-induced phosphorylation of Akt2 greater than Akt1. Since lipid phosphatases SH2-containing inositol 5'-phoshatase 2 (SHIP2) and phosphatase and tensin homologs deleted on chromosome 10 (PTEN) are negative regulators of insulin's metabolic signaling at the step downstream of phosphatidylinositol 3-kinase, we investigated the Akt isoform-specific properties of these phosphatases in the negative regulation after short- and long-term insulin treatment and examined the influence of inhibition on the amelioration of insulin resistance caused by TNF-alpha in 3T3-L1 adipocytes. Adenovirus-mediated overexpression of WT-SHIP2 decreased the phosphorylation of Akt2 greater than Akt1 after insulin stimulation up to 15 min. Expression of a dominant-negative DeltaIP-SHIP2 enhanced the phosphorylation of Akt2 up to 120 min. On the other hand, overexpression of WT-PTEN inhibited the phosphorylation of both Akt1 and Akt2 after short- but not long-term insulin treatment. The expression of DeltaIP-PTEN enhanced the phosphorylation of Akt1 at 120 min and that of Akt2 at 2 min. Interestingly, the expression of DeltaIP-SHIP2, but not DeltaIP-PTEN, protected against the TNF-alpha inhibition of insulin-induced phosphorylation of Akt2, GSK3, and AS160, whereas both improved the TNF-alpha inhibition of insulin-induced 2-deoxyglucose uptake. The results indicate that these lipid phosphatases possess different characteristics according to the time and preference of Akt isoform-dependent signaling in the negative regulation of the metabolic actions of insulin, whereas both inhibitions are effective in the amelioration of insulin resistance caused by TNF-alpha.
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PMID:Impact of lipid phosphatases SHIP2 and PTEN on the time- and Akt-isoform-specific amelioration of TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. 1900 49

Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. Nur77 is highly expressed in vascular endothelial cells (ECs) and plays a role in the regulation of cell proliferation and angiogenesis; its role in vascular inflammation, however, remains unknown. Treatment of human umbilical vein ECs (HUVECs) with tumor necrosis factor (TNF)-alpha substantially increased the transcription and protein expression of Nur77 in a dose and time-dependent manner, as determined by Northern blot and Western blot analysis. Adenovirus mediated overexpression of Nur77 markedly increased the intracellular levels of IkappaBalpha by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on IkappaBalpha expression, suggesting that Nur77 is an important transcriptional factor in controlling IkappaBalpha expression in ECs. Furthermore, overexpression of Nur77 significantly increased IkappaBalpha promoter activity via directly binding to a Nur77 response element in the IkappaBalpha promoter. Importantly, overexpression of Nur77, but not DN-Nur77, protected ECs against the TNF-alpha- and interleukin-1beta-induced endothelial activation, as characterized by attenuation in the nuclear factor kappaB activation, expression of adhesion molecules ICAM-1 and VCAM-1, and monocytic adherence to ECs. These results indicate that Nur77 negatively regulates the TNF-alpha- and interleukin-1beta-induced vascular EC activation by transcriptionally upregulation of IkappaBalpha expression.
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PMID:The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression. 1932 55

The fat-derived hormone adiponectin has been shown to have a protective role in macrovascular disorders. However, nothing is known about the function of adiponectin in retinal microvessel disease. Here, we investigated the causal role of adiponectin in retinal vessel formation and inflammation under conditions of hypoxia. When neonatal mice were subjected to ischemia-induced retinopathy, pathological retinal neovascularization during ischemia was exacerbated in adiponectin-knockout (APN-KO) mice compared with wild-type mice (neovascular area: 17.0+/-1.0% versus 11.7+/-0.6%, respectively). APN-KO mice also exhibited increased leukocyte adhesion (2.3+/-0.4-fold) and tumor necrosis factor (TNF)-alpha expression (2.6+/-0.2-fold) in hypoxic retina. Adenovirus-mediated overexpression of adiponectin attenuated hypoxia-induced pathological retinal neovascularization by 35% in wild-type mice and by 40% in APN-KO mice and leukostasis by 64% in wild-type mice and by 75% in APN-KO mice, which were associated with reduced TNF-alpha production. TNF-alpha blockade diminished the enhanced pathological neovascularization in APN-KO mice by 34%, and the inhibitory effects of adiponectin overexpression on retinal neovascularization and leukocyte adhesion were abolished in mice lacking TNF-alpha. These data provide evidence that adiponectin protects against retinal vessel injury following pathological stimuli through modulation of TNF-alpha inflammatory responses.
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PMID:Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. 1942 59

Although viral gene transfer is efficient in achieving transgene expression for tissue engineering, drawbacks of virus dissemination, toxicity and transient gene expression due to immune response have hindered its widespread application. Many tissue engineering studies thus opt to genetically engineer cells in vitro prior to their introduction in vivo. However, it would be attractive to obviate the need for in vitro manipulation by transducing the infiltrating progenitor cells in situ. This study introduces the fabrication of a virus-encapsulated electrospun fibrous scaffold to achieve sustained and localized transduction. Adenovirus encoding the gene for green fluorescent protein was efficiently encapsulated into the core of poly(epsilon-caprolactone) fibers through co-axial electrospinning and was subsequently released via a porogen-mediated process. HEK 293 cells seeded on the scaffolds expressed high level of transgene expression over a month, while cells inoculated by scaffold supernatant showed only transient expression for a week. RAW 264.7 cells cultured on the virus-encapsulated fibers produced a lower level of IL-1 beta, TNF-alpha and IFN-alpha, suggesting that the activation of macrophage cells by the viral vector was reduced when encapsulated in the core-shell PCL fibers. In demonstrating sustained and localized cell transduction, this study presents an attractive alternative mode of applying viral gene transfer for regenerative medicine.
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PMID:Sustained viral gene delivery through core-shell fibers. 1953 80


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