scholarly journals Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

2012 ◽  
Vol 209 (11) ◽  
pp. 1919-1935 ◽  
Author(s):  
Abdul G. Hameed ◽  
Nadine D. Arnold ◽  
Janet Chamberlain ◽  
Josephine A. Pickworth ◽  
Claudia Paiva ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Vascular Remodeling ◽  
Tumor Necrosis ◽  
Pulmonary Arteries ◽  
Systemic Circulation ◽  
Vascular Lesions ◽  
Rodent Models ◽  
Antibody Treatment ◽  
Pulmonary Vascular Remodeling ◽  
Necrosis Factor

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies.

scholarly journals The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia

2021 ◽  
Vol 406 ◽  
pp. 113229
Author(s):  
Heath W. Shelton ◽  
S. Prasad Gabbita ◽  
W. Drew Gill ◽  
Katherine C. Burgess ◽  
Wyatt S. Whicker ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Prepulse Inhibition ◽  
Tumor Necrosis ◽  
Microglial Activation ◽  
Tnf Alpha ◽  
Rodent Models ◽  
Necrosis Factor

TUMOR NECROSIS FACTOR ANTIBODY TREATMENT OF SEPTIC BABOONS REDUCES THE PRODUCTION OF SUSTAINED T-CELL SUPPRESSIVE FACTORS

Shock ◽  
1995 ◽  
Vol 3 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Wolfgang G. Junger ◽  
David B. Hoyt ◽  
Heinz Redl ◽  
Forrest C. Liu ◽  
William H. Loomis ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Antibody Treatment ◽  
Necrosis Factor

Systemic anti-tumor necrosis factor antibody treatment exacerbates endotoxin-induced uveitis in the rat

1995 ◽  
Vol 61 (6) ◽  
pp. 667-675 ◽  
Author(s):  
Alex F. De Vos ◽  
Mariette A.C. Van Haren ◽  
Cora Verhagen ◽  
Rick Hoekzema ◽  
Aize Kijlstra
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Antibody Treatment ◽  
Necrosis Factor

scholarly journals Suppression of Transmembrane Tumor Necrosis Factor Alpha Processing by a Specific Antibody Protects Against Colitis-Associated Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongping Ba ◽  
Rui Jiang ◽  
Meng Zhang ◽  
Bingjiao Yin ◽  
Jing Wang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Time Window ◽  
Suppressor Cells ◽  
Tumor Stage ◽  
Pathological Process ◽  
Antibody Treatment ◽  
Necrosis Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Soluble tumor necrosis factor-α (sTNF-α) plays an important role in colitis-associated cancer (CAC); however, little is known about transmembrane TNF-α (tmTNF-α). Here, we observed an increase in sTNF-α mainly in colitis tissues from an azoxymethane/dextran sodium sulfate (DSS)-induced CAC mouse model whereas tmTNF-α levels were chiefly increased on epithelial cells at the tumor stage. The ratio of intracolonic tmTNF-α/sTNF-α was negatively correlated with the levels of pro-inflammatory mediators (IL-1β, IL-6, and NO) and M1 macrophages but positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and the level of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect of tmTNF-α. This effect of tmTNF-α was confirmed again by the induction of resistance to LPS in colonic epithelial cell lines NCM460 and HCoEpiC through the addition of exogenous tmTNF-α or transfection of the tmTNF-α leading sequence that lacks the extracellular segment but retains the intracellular domain of tmTNF-α. A tmTNF-α antibody was used to block tmTNF-α shedding after the first or second round of inflammation induction by DSS drinking to shift the time window of tmTNF-α expression ahead to the inflammation stage. Antibody treatment significantly alleviated inflammation and suppressed subsequent adenoma formation, accompanied by increased apoptosis. An antitumor effect was also observed when the antibody was administered at the malignant phase of CAC. Our results reveal tmTNF-α as a novel molecular marker for malignant transformation in CAC and provide a new insight into blocking the pathological process by targeting tmTNF-α processing.

Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12

2001 ◽  
Vol 280 (6) ◽  
pp. L1128-L1137 ◽  
Author(s):  
Takashige Maeyama ◽  
Kazuyoshi Kuwano ◽  
Masayuki Kawasaki ◽  
Ritsuko Kunitake ◽  
Naoki Hagimoto ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Lung Tissue ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
T Helper ◽  
Antibody Treatment ◽  
Factor Α ◽  
Necrosis Factor ◽  
Helper Type

We previously demonstrated essential roles of the Fas-Fas ligand (FasL) pathway in bleomycin-induced pneumopathy in mice. T lymphocytes and natural killer cells express FasL on activation and use it as a cytotoxic effector molecule. Because interleukin (IL)-12 is known to play a critical role in cell-mediated immunity, we investigated whether anti-IL-12 antibody treatment suppresses the development of this model. The anti-IL-12 antibody treatment decreased the number of apoptotic cells and the degree of inflammation and fibrosis in lung tissue. The results of RT-PCR showed that IL-12p40, IL-12 receptor (R) β2, interferon-γ, tumor necrosis factor-α and FasL mRNAs were upregulated after bleomycin instillation. The upregulation of FasL, IL-12Rβ2, and tumor necrosis factor-α mRNA expression in lung tissue was suppressed by anti-IL-12 antibody treatment. The results of enzyme-linked immunosorbent assay showed that the levels of IL-12p40, but not of IL-12p70, were increased in lung tissue after bleomycin instillation. Although the increase in IL-12Rβ2 mRNA levels suggests that the T helper type 1 cell response may participate in lung injury, the increase in IL-12p40 supports T helper type 2 cell predominance in the fibrotic process of this model. The administration of anti-IL-12 antibody could be a novel therapy against lung injury and pulmonary fibrosis.

Tacrolimus Salvage in Anti–Tumor Necrosis Factor Antibody Treatment-Refractory Crohn’s Disease

2013 ◽  
Vol 19 (6) ◽  
pp. 1107-1111 ◽  
Author(s):  
Mark E. Gerich ◽  
Darrell S. Pardi ◽  
David H. Bruining ◽  
Patricia P. Kammer ◽  
Brenda D. Becker ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Tumor Necrosis Factor ◽  
Crohn's Disease ◽  
Tumor Necrosis ◽  
Antibody Treatment ◽  
Treatment Refractory ◽  
Necrosis Factor

scholarly journals Kinetics of Endotoxin and Tumor Necrosis Factor Appearance in Portal and Systemic Circulation After Hemorrhagic Shock in Rats

1995 ◽  
Vol 221 (1) ◽  
pp. 100-106 ◽  
Author(s):  
Jianxin Jiang ◽  
Soheyl Bahrami ◽  
Guenther Leichtfried ◽  
Heinz Redl ◽  
Wolfgang Öhlinger ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Hemorrhagic Shock ◽  
Tumor Necrosis ◽  
Systemic Circulation ◽  
Kinetics Of ◽  
Necrosis Factor

Shiga Toxin Type 1 Activates Tumor Necrosis Factor-α Gene Transcription and Nuclear Translocation of the Transcriptional Activators Nuclear Factor-κB and Activator Protein-1

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 558-566 ◽  
Author(s):  
Ramesh Sakiri ◽  
Belakere Ramegowda ◽  
Vernon L. Tesh
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Translocation ◽  
Vascular Lesions ◽  
Transcriptional Activators ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Shiga toxins (Stxs) produced by Shigella dysenteriae 1 andEscherichia coli have been implicated in the pathogenesis of bloody diarrhea, acute renal failure, and neurologic abnormalities. The pathologic hallmark of Stx-mediated tissue damage is the development of vascular lesions in which endothelial cells are swollen and detached from underlying basement membranes. However, in vitro studies using human vascular endothelial cells demonstrated minimal Stx-induced cytopathic effects, unless the target cells were also incubated with the proinflammatory cytokines tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). These cytokines have been shown to upregulate the expression of the Stx-binding membrane glycolipid globotriaosylceramide (Gb3). We show here that purified Stx1 induces TNF secretion by a human monocytic cell line, THP-1, in a dose- and time-dependent manner. Treatment of cells with both lipopolysaccharides (LPS) and Stx1 results in augmented TNF production. Treatment with the nontoxic Gb3-binding subunit of Stx1 or with an anti-Gb3 monoclonal antibody did not trigger TNF production. Northern blot analyses show that Stx1 causes increased TNF-α production through transcriptional activation. Increased levels of TNF-α mRNA are preceded by the nuclear translocation of the transcriptional activators NF-κB and AP-1 and the loss of cytoplasmic IκB-α. These data are the first to show that, in addition to direct cytotoxicity, Stxs possess cellular signaling capabilities sufficient to induce the synthesis of cytokines that may be necessary for target cell sensitization and the development of vascular lesions.

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