scholarly journals Tumour necrosis factor signalling in health and disease

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 111 ◽  
Author(s):  
Jonathan Holbrook ◽  
Samuel Lara-Reyna ◽  
Heledd Jarosz-Griffiths ◽  
Michael F. McDermott
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Short Review ◽  
Vital Role ◽  
Signalling Pathways ◽  
Cellular Effects ◽  
Disease States ◽  
Downstream Effects ◽  
Health And Disease ◽  
Necrosis Factor

The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involvement as well as cellular activation with subsequent proliferation and programmed cell death or necrosis. As might be expected with such a broad spectrum of cellular effects and complex signalling pathways, TNF has also been implicated in a number of disease states, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Since the time of its discovery over 40 years ago, TNF ligand and its receptors, TNF receptor (TNFR) 1 and 2, have been categorised into two complementary superfamilies, namely TNF (TNFSF) and TNFR (TNFRSF), and 19 ligands and 29 receptors have been identified to date. There have been significant advances in our understanding of TNF signalling pathways in the last decade, and this short review aims to elucidate some of the most recent advances involving TNF signalling in health and disease.

scholarly journals Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4250
Author(s):  
Antonio Ahn ◽  
Euan J. Rodger ◽  
Jyoti Motwani ◽  
Gregory Gimenez ◽  
Peter A. Stockwell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Targeted Therapy ◽  
Tumour Necrosis Factor ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Tumour Necrosis ◽  
Melanoma Cells ◽  
Signalling Pathways ◽  
Necrosis Factor ◽  
Melanoma Cell Lines

Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumour necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.

P3509Leukocyte derived tumour necrosis factor modulates cardiac function in health and disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Walker ◽  
A Gutierrez Del Arroyo ◽  
J Sanchez ◽  
G L Ackland
Keyword(s):  
Ejection Fraction ◽  
Cardiac Function ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cardiac Injury ◽  
Cardiac Cells ◽  
Health And Disease ◽  
Deficient Mice ◽  
Necrosis Factor

Abstract Purpose Tumour necrosis factor alpha (TNFα) regulates both normal and pathophysiological cardiac function. The regulatory role of TNFα derived from different sources (leukocyte versus cardiac cells) in cardiac physiology is unclear. Deficiency of iRhom2 protein prevents circulating immune cells from shedding TNFα (and CD62L, an adhesion molecule essential for effective immune function). Here we investigated the role of leukocyte derived TNFα in constitutive cardiac function and after cardiac injury. Methods Adult iRhom2-deficient mice (KO) and wildtype (Wt) littermates, of both genders, underwent echocardiography to assess cardiac physiologic function at least 1 week before receiving a single dose of isoproterenol (300mg/kg IP) to induce cellular death in 10% of the cardiomyoctes [1]. Cardiac echocardiography was repeated 36 hours after isoproterenol. Peripheral and cardiac-resident leukocytes were phenotyped by flow cytometry and molecular markers of cardiac stress (atrial and brain natriuretic protein, ANP, BNP) and inflammation (NFkB) were quantified using RT-PCR. Results Peripheral leukocytes from iRhom2 KO mice failed to shed CD62L in response to isoproterenol induced cardiac injury (e.g. neutrophils CD62L Mean Fluorescence Intensity KO: 9149±4616, Wt: 972±558, p<0.0001, n=9). iRhom2-deficient mice had higher cardiac output at baseline (KO 23±2 mL/min, n=11) compared to their wildtype littermates (Wt 18±3 mL/min, n=9). Wild type mice increased contractility after isoproterenol (Wt ejection fraction: baseline 60±6%, isoproterenol 68±6%, n=8) whilst iRhom2-deficient mice were unable to (KO ejection fraction: baseline 66±9%, isoproterenol 61±5%, n=8). ANP and BNP mRNA were elevated in ventricular tissue of iRhom2-knockout mice after isoproterenol, when compared to naïve tissue (ANP 2ΔCT: 3x increase, BNP 2ΔCT: 1.6x increase) whereas only ANP was elevated in wildtypes (ANP 2ΔCT: 2.7x increase, BNP 2ΔCT: 0.9x increase). No difference in immune cell infiltration of ventricular cardiac tissue was observed (number of CD45+ cells KO: 3014±3482, Wt: 2555±1411, p=0.7, n=9) NFkB mRNA was upregulated at baseline (2ΔCT KO: 0.2±0.08, Wt: 0.1±0.09) suggesting constitutive cardiac inflammation in iRhom2-deficient mice. Conclusions Inability to shed CD62L and TNFα is associated with constitutive and acquired cardiac dysfunction in iRhom2-deficient mice. These data support the hypothesis that leukocyte-derived TNFα is required for maintaining cardiac function in health and disease. Acknowledgement/Funding National Institute of Academic Anaesthesia/Royal College of Anaesthetists/British Journal of Anaesthesia; National Institute for Health Research

Substrate specificity and inducibility of TACE (tumour necrosis factor α-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity

2003 ◽  
Vol 70 ◽  
pp. 39-52 ◽  
Author(s):  
Roy A. Black ◽  
John R. Doedens ◽  
Rajeev Mahimkar ◽  
Richard Johnson ◽  
Lin Guo ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Recent Work ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Transforming Growth Factor ◽  
Intrinsic Activity ◽  
Converting Enzyme ◽  
Tumour Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

Tumour necrosis factor α (TNFα)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor α, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.

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