TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD

Bikker, Rolf; Christmann, Martin; Preuß, Katharina; Welz, Bastian; Friesenhagen, Judith; Dittrich–Breiholz, Oliver; Huber, René; Brand, Korbinian

doi:10.1016/j.cellsig.2017.06.009

Cited by 19 publications

(31 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been further shown that a GSK3 inhibitor can suppress the rapid resynthesis and nuclear accumulation of IκBα that occurs during LPS stimulation following TNF preincubation, suggesting that GSK3 is involved in the IκBα-mediated restriction of NF-κB signaling under these conditions [288]. In addition, GSK3 inhibition in TNF-tolerized cells also results in increased binding of p65 at the promoters of tolerizable genes (e.g., IL-6), reduced expression of A20 (a negative regulator of NF-κB signaling, e.g., during TNF incubation [291]), and enhanced chromatin accessibility [288]. Recently, it has further been demonstrated that numerous proteins differentially phosphorylated under conditions inducing high-dose TNF tolerance are potential GSK3 targets [259].…”

Section: Inhibition Of Gsk3 and The Perpetuation Of Inflammationmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

Self Cite

102

View full text Add to dashboard Cite

GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

show abstract

Section: Inhibition Of Gsk3 and The Perpetuation Of Inflammationmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

Self Cite

102

View full text Add to dashboard Cite

show abstract

“…Following restimulation, however, no further stimulus-induced proteolysis of I κ B α can be observed. Consistently, it has also been observed that I κ B kinase (IKK) phosphorylation is completely inhibited in high-dose pretreated and restimulated cells when compared to naïve cells [ 4 , 36 ]. In TNF-overexpressing murine cardiomyocytes, additional activation of p50 homodimers has also been found in comparison to control cells and it was speculated that this effect might represent an adaptive response to reduce the detrimental inflammatory consequences of the permanent presence of TNF [ 11 ].…”

Section: Molecular Characteristicsmentioning

confidence: 71%

“…A20 is a ubiquitinase/deubiquitinase known for its role as a repressor of NF- κ B signaling [ 37 , 38 ] and characterized by three major functionalities, that is, noncatalytic mechanisms mediating the repression of IKK activation, ubiquitin ligase activity leading to K48-labeling of proteins such as receptor interacting protein (RIP) to induce their proteasomal degradation, and protease activity towards K63 and M1 polyubiquitins [ 39 ]. A20 mRNA and protein amounts are markedly upregulated in THP-1 cells as well as primary human monocytes and macrophages pretreated with high TNF doses [ 4 , 36 ], an effect equivalently occurring in cross-tolerance [ 6 ]. The siRNA-dependent knockdown of A20 leads to a strong upregulation of IKK phosphorylation and proinflammatory gene expression in monocytic cells in which TNF tolerance was induced by a high TNF dose [ 4 , 36 ] indicating that A20 is a major regulator of high-dose-induced tolerance ( Figure 3 ).…”

Section: Molecular Characteristicsmentioning

confidence: 99%

TNF Tolerance in Monocytes and Macrophages: Characteristics and Molecular Mechanisms

Huber

Bikker

Welz

et al. 2017

Journal of Immunology Research

Self Cite

View full text Add to dashboard Cite

Tumor necrosis factor (TNF) tolerance in monocytes and macrophages means that preexposure to TNF reduces the sensitivity in these cells to a subsequent restimulation with this cytokine. Differential effects arise following preincubation with both low and high doses of TNF resulting in absolute as well as induction tolerance affecting specific immunologically relevant gene sets. In this review article, we summarize the relevance of TNF tolerance in vivo and the molecular mechanisms underlying these forms of tolerance including the role of transcription factors and signaling systems. In addition, the characteristics of cross-tolerance between TNF and lipopolysaccharide (LPS) as well as pathophysiological aspects of TNF tolerance are discussed. We conclude that TNF tolerance may represent a protective mechanism involved in the termination of inflammation and preventing excessive or prolonged inflammation. Otherwise, tolerance may also be a trigger of immune paralysis thus contributing to severe inflammatory diseases such as sepsis. An improved understanding of TNF tolerance will presumably facilitate the implementation of diagnostic or therapeutic approaches to more precisely assess and treat inflammation-related diseases.

show abstract

“…In the NF-κB signaling pathway, TNFAIP3 resists TNF-induced NF-κB signaling by replacing K48-linked polyubiquitin chains with K63-linked polyubiquitin chains to terminate the receptor interacting protein1 (RIP1) interaction with NF-κB essential modulator (NEMO) [34], thus ultimately limiting the inflammatory responses induced by many pattern recognition receptors such as TLRs [32,35]. The preventive roles of TNFAIP3 have been widely reported in a number of systemic inflammatory diseases, such as rheumatoid arthritis, autoimmune diseases, gastrointestinal and hepatic disorders, psoriasis, aging, and cancer [36], and also in different viral infections such as measles virus [37], influenza virus [38], and parasitic infection like Leishmania donovani [38]. In the interface of host-microbe interaction, TNFAIP3 most likely acts as an inhibitory modulator in disease pathophysiology [39].…”

Section: Discussionmentioning

confidence: 99%

Decrease of miR-19b-3p in Brain Microvascular Endothelial Cells Attenuates Meningitic Escherichia coli-Induced Neuroinflammation via TNFAIP3-Mediated NF-κB Inhibition

Amjad

Yang

et al. 2019

Pathogens

View full text Add to dashboard Cite

Meningitic Escherichia coli can traverse the host’s blood–brain barrier (BBB) and induce severe neuroinflammatory damage to the central nervous system (CNS). During this process, the host needs to reasonably balance the battle between bacteria and brain microvascular endothelial cells (BMECs) to minimize inflammatory damage, but this quenching of neuroinflammatory responses at the BBB is unclear. MicroRNAs (miRNAs) are widely recognized as key negative regulators in many pathophysiological processes, including inflammatory responses. Our previous transcriptome sequencing revealed numbers of differential miRNAs in BMECs upon meningitic E. coli infection; we next sought to explore whether and how these miRNAs worked to modulate neuroinflammatory responses at meningitic E. coli entry of the BBB. Here, we demonstrated in vivo and in vitro that meningitic E. coli infection of BMECs significantly downregulated miR-19b-3p, which led to attenuated production of proinflammatory cytokines and chemokines via increasing the expression of TNFAIP3, a negative regulator of NF-κB signaling. Moreover, in vivo injection of miR-19b-3p mimics during meningitic E. coli challenge further aggravated the inflammatory damage to mice brains. These in vivo and in vitro findings indicate a novel quenching mechanism of the host by attenuating miR-19b-3p/TNFAIP3/NF-κB signaling in BMECs in response to meningitic E. coli, thus preventing CNS from further neuroinflammatory damage.

show abstract

TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD

Cited by 19 publications

References 46 publications

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

TNF Tolerance in Monocytes and Macrophages: Characteristics and Molecular Mechanisms

Decrease of miR-19b-3p in Brain Microvascular Endothelial Cells Attenuates Meningitic Escherichia coli-Induced Neuroinflammation via TNFAIP3-Mediated NF-κB Inhibition

Contact Info

Product

Resources

About