scholarly journals Redundancy in Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) Signaling In Vivo: Mice with Inactivation of the Entire TNF/LT Locus versus Single-Knockout Mice

2002 ◽  
Vol 22 (24) ◽  
pp. 8626-8634 ◽  
Author(s):  
Dmitry V. Kuprash ◽  
Marat B. Alimzhanov ◽  
Alexei V. Tumanov ◽  
Sergei I. Grivennikov ◽  
Alexander N. Shakhov ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Knockout Mice ◽  
Tumor Necrosis ◽  
Target Genes ◽  
Recombination System ◽  
Major Histocompatibility Complex Locus ◽  
Cell Compartmentalization ◽  
Necrosis Factor ◽  
Single Knockout

ABSTRACT Homologous genes and gene products often have redundant physiological functions. Members of the tumor necrosis factor (TNF) family of cytokines can signal activation, proliferation, differentiation, costimulation, inhibition, or cell death, depending on the type and status of the target cell. TNF, lymphotoxin α (LTα), and LTβ form a subfamily of a larger family of TNF-related ligands with their genes being linked within a compact 12-kb cluster inside the major histocompatibility complex locus. Singly TNF-, LTα-, and LTβ-deficient mice share several phenotypic features, suggesting that TNF/LT signaling pathways may regulate overlapping sets of target genes. In order to directly address the issue of redundancy of TNF/LT signaling, we used the Cre-loxP recombination system to create mice with a deletion of the entire TNF/LT locus. Mice with a triple LTβ/TNF/LTα deficiency essentially manifest a combination of LT and TNF single-knockout phenotypes, except for microarchitecture of the spleen, where the disorder of lymphoid cell positioning and functional T- and B-cell compartmentalization is severer than that found in TNF or LT single-knockout mice. Thus, our data support the notion that TNF and LT have largely nonredundant functions in vivo.

Inhibition of PPAR-α activity in mice with cardiac-restricted expression of tumor necrosis factor: potential role of TGF-β/Smad3

2007 ◽  
Vol 292 (3) ◽  
pp. H1443-H1451 ◽  
Author(s):  
Kenichi Sekiguchi ◽  
Qi Tian ◽  
Masakuni Ishiyama ◽  
Jana Burchfield ◽  
Feng Gao ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Α Activity ◽  
Necrosis Factor

A shift in energy substrate utilization from fatty acids to glucose has been reported in failing hearts, resulting in improved oxygen efficiency yet perhaps also contributing to a state of energy deficiency. Peroxisome proliferator-activated receptor (PPAR)-α, the principal transcriptional regulator of cardiac fatty acid β-oxidation (FAO) genes, is downregulated in heart failure, and this may contribute to reduced fatty acid utilization. Cardiomyopathic states are also accompanied by elevated levels of circulating cytokines, such as tumor necrosis factor (TNF), as well as increased local production of cytokines and profibrotic factors, such as transforming growth factor (TGF)-β. However, whether these molecular pathways directly modulate cardiac energy metabolism and PPAR-α activity is not known. Therefore, FAO capacity and FAO gene expression were determined in mice with cardiac-restricted overexpression of TNF (MHCsTNF3). MHCsTNF3 hearts had significantly lower FAO capacity and decreased expression of PPAR-α and FAO target genes compared with control hearts. Surprisingly, TNF had little effect on PPAR-α activity and FAO rates in cultured ventricular myocytes, suggesting that TNF acts indirectly on myocyte FAO in vivo. We found that TGF-β expression was upregulated in MHCsTNF3 hearts and that treatment of cultured myocytes with TGF-β significantly suppressed FAO rates and directly impaired PPAR-α activity, a result reproduced by Smad3 overexpression. This work demonstrates that TGF-β signaling pathways directly suppress PPAR-α activity and reduce FAO in cardiac myocytes, perhaps in response to locally elevated TNF. Although speculative, TGF-β-driven repair mechanisms may also include the additional benefit of limiting FAO in injured myocardium.

scholarly journals Multiple effects of tumor necrosis factor on lipoprotein lipase in vivo.

1987 ◽  
Vol 262 (17) ◽  
pp. 8390-8394 ◽  
Author(s):  
H Semb ◽  
J Peterson ◽  
J Tavernier ◽  
T Olivecrona
Keyword(s):  
Tumor Necrosis Factor ◽  
Lipoprotein Lipase ◽  
Tumor Necrosis ◽  
Necrosis Factor

Chylomicron-bound LPS inhibits tumor necrosis factor-induced capillary leak in vivo

2004 ◽  
Vol 121 (2) ◽  
pp. 276
Author(s):  
A.L. Spitzer ◽  
G.P. Victorino ◽  
F. Kasravi ◽  
B. Curran ◽  
J. Chang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Capillary Leak ◽  
Necrosis Factor

Abstract 354: Lower Circulating Levels of Tumor Necrosis Factor Related Apoptosis-inducing Ligand (TRAIL) are Associated with Increased Sub-clinical Coronary Atherosclerosis among Smokers

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aman Gupta ◽  
Divay Chandra ◽  
Yingze Zhang ◽  
Steven Reis ◽  
Frank Sciurba
Keyword(s):  
Tumor Necrosis Factor ◽  
Coronary Atherosclerosis ◽  
Tumor Necrosis ◽  
Smoking Status ◽  
Calcium Score ◽  
Meso Scale Discovery ◽  
The Mean ◽  
Necrosis Factor

Rationale: There is significant in vitro evidence demonstrating anti-atherogenic effect of circulating Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Also, decreased circulating TRAIL levels have been reported in patients with acute myocardial infarction and in those undergoing coronary catheterization due to suspected coronary atherosclerosis. However, it remains unknown if TRAIL levels are associated with sub-clinical coronary atherosclerosis. Methods: The study included 460 current and former smokers enrolled in the Pittsburgh COPD SCCOR study. Serum TRAIL levels were measured by electrochemiluminescence immunoassay, according to the manufacture’s protocol (Meso Scale Discovery, Gaithersburg, Maryland). Coronary atherosclerosis was assessed by a validated visual coronary artery calcium scoring system using non-EKG gated chest CT scans (Weston score). Ordinal logistic regression models were used to identify significant associations between categories of CAC score (0, 1-3, 4-8, and 9-12) and TRAIL level, and to adjust for cardiovascular risk factors. Results: The mean age of the 460 participants was 65.7 ± 6.3 years, 52.2% were male, and the mean pack years of smoking was 55.0 ± 30.8 years. In univariate analyses, each standard deviation decrease in TRAIL levels was associated with 1.42-fold increase in the odds of having calcium scores in one higher category (p<0.001). This association persisted despite adjustment for age, gender, race, body mass index, hypertension, diabetes, hyperlipidemia, pack years of smoking, and current smoking status (adjusted OR for higher category of calcium score per SD decrease in TRAIL level 1.22, p=0.04). Conclusions: Our results expand on the in vitro and in vivo data linking decreased TRAIL levels with increased atherosclerosis by demonstrating a novel association between lower circulating TRAIL and increased subclinical coronary atherosclerosis.

scholarly journals In Vivo and in Vitro Evidence for the Involvement of Tumor Necrosis Factor-α in the Induction of Leptin by Lipopolysaccharide*

Endocrinology ◽  
1998 ◽  
Vol 139 (5) ◽  
pp. 2278-2283 ◽  
Author(s):  
Brian N. Finck ◽  
Keith W. Kelley ◽  
Robert Dantzer ◽  
Rodney W. Johnson
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo

2005 ◽  
Vol 25 (8) ◽  
pp. 3348-3356 ◽  
Author(s):  
Dietrich B. Conze ◽  
Lori Albert ◽  
David A. Ferrick ◽  
David V. Goeddel ◽  
Wen-Chen Yeh ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Homologous Gene ◽  
Necrosis Factor Alpha ◽  
Ubiquitin Protein Ligase ◽  
Signaling Complex ◽  
Subsequent Degradation ◽  
Necrosis Factor

ABSTRACT Inhibitor of apoptosis proteins (IAPs) c-IAP1 and c-IAP2 were identified as part of the tumor necrosis factor receptor 2 (TNFR2) signaling complex and have been implicated as intermediaries in tumor necrosis factor alpha signaling. Like all RING domain-containing IAPs, c-IAP1 and c-IAP2 have ubiquitin protein ligase (E3) activity. To explore the function of c-IAP1 in a physiologic setting, c-IAP1-deficient mice were generated by homologous gene recombination. These animals are viable and have no obvious sensitization to proapoptotic stimuli. Cells from c-IAP1−/− mice do, however, express markedly elevated levels of c-IAP2 protein in the absence of increased c-IAP2 mRNA. In contrast to reports implicating c-IAPs in the activation of NF-κB, resting and cytokine-induced NF-κB activation was not impaired in c-IAP1-deficient cells. Transient transfection studies with wild-type and E3-defective c-IAP1 revealed that c-IAP2 is a direct target for c-IAP1-mediated ubiquitination and subsequent degradation, which are potentiated by the adaptor function of TRAF2. Thus, the c-IAPs represent a pair of TNFR-associated ubiquitin protein ligases in which one regulates the expression of the other by a posttranscriptional and E3-dependent mechanism.

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