scholarly journals Inhibitory feedback control of NF-κB signalling in health and disease

2021 ◽  
Vol 478 (13) ◽  
pp. 2619-2664
Author(s):  
Jack A. Prescott ◽  
Jennifer P. Mitchell ◽  
Simon J. Cook

Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and ‘re-set’ inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical ‘inhibitor of κB kinases’ (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors.

1994 ◽  
Vol 126 (1) ◽  
pp. 189-198 ◽  
Author(s):  
G Sluder ◽  
F J Miller ◽  
E A Thompson ◽  
D E Wolf

To help ensure the fidelity of chromosome transmission during mitosis, sea urchin zygotes have feedback control mechanisms for the metaphase-anaphase transition that monitor the assembly of spindle microtubules and the complete absence of proper chromosome attachment to the spindle. The way in which these feedback controls work has not been known. In this study we directly test the proposal that these controls operate by maloriented chromosomes producing a diffusible inhibitor of the metaphase-anaphase transition. We show that zygotes having 50% of their chromosomes (approximately 20) unattached or monoriented initiate anaphase at the same time as the controls, a time that is well within the maximum period these zygotes will spend in mitosis. In vivo observations of the unattached maternal chromosomes indicate that they are functionally within the sphere of influence of the molecular events that cause chromosome disjunction in the spindle. Although the unattached chromosomes disjoin (anaphase onset without chromosome movement) several minutes after spindle anaphase onset, their disjunction is correlated with the time of spindle anaphase onset, not the time their nucleus breaks down. This suggests that the molecular events that trigger chromosome disjunction originate in the central spindle and propagate outward. Our results show that the mechanisms for the feedback control of the metaphase-anaphase transition in sea urchin zygotes do not involve a diffusible inhibitor produced by maloriented chromosomes. Even though the feedback controls for the metaphase-anaphase transition may detect the complete absence of properly attached chromosomes, they are insensitive to unattached or mono-oriented chromosomes as long as some chromosomes are properly attached to the spindle.


1974 ◽  
Vol 76 (3) ◽  
pp. 556-569 ◽  
Author(s):  
E. Nieschlag ◽  
K. H. Usadel ◽  
H. K. Kley ◽  
U. Schwedes ◽  
K. Schöffling ◽  
...  

ABSTRACT A new method for the investigation of hypothalamo-pituitary-gonadal and adrenal feedback control mechanisms based on the biological neutralization of gonadal and adrenal steroids by active immunization is proposed. The regulatory influence of a given steroid in the feedback control is proved when reduction of the free, biologically active fraction of this steroid caused by antibody binding induces a positive response of the pituitary, thus effecting gonadal or adrenal hypertrophy and hyperfunction. The advantages and limitations of the new model are demonstrated by the effects of active immunization of rabbits with cortisol (F), aldosterone (Aldo), dehydroepiandrosterone (DHA), androstenedione (Δ4-A), testosterone (T), 5α-dihydrotestosterone (5α-DHT), 5β-DHT and oestradiol (E2). In the immunized animals and in a control group serum concentrations of total corticosteroids (TC), DHA, T, Δ4-A, E1, E2, LH and FSH, the percentage of binding of steroids in serum and the specificity of the antisera are determined. The testes are evaluated by histometry and the nuclear volume of the adrenocortical and Leydig cells is measured.


2021 ◽  
Author(s):  
Nikki D. Russell ◽  
Clement Y. Chow

AbstractGenotype x Environment (GxE) interactions occur when environmental conditions drastically change the effect of a genetic variant. In order to truly understand the effect of genetic variation, we need to incorporate multiple environments into our analyses. Many variants, under steady state conditions, may be silent or even have the opposite effect under stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with tissue type and cellular stress. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to return the cell to homeostasis. This transcriptional response, despite being a well conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study GxE effects. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans-regulatory mechanisms underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. Genotype-dependent ER stress-responsive genes are enriched for processes such as protein folding, apoptosis, and protein transport, indicating that some of the variability occurs in canonical ER stress factors. The majority of regulatory mechanisms underlying these variable transcriptional responses derive from cis-regulatory variation and are unique to a given tissue or ER stress state. This study demonstrates the need for incorporating multiple environments in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.Author SummaryThe effect of genetic variation is dependent on environmental context. Here we use genetically diverse mouse strains to understand how genetic variation interacts with stress state to produce variable transcriptional profiles. In this study, we take advantage of the endoplasmic reticulum (ER) stress response which is a large transcriptional response to misfolded proteins. Using this system, we uncovered tissue- and ER stress-specific effects of genetic variation on gene expression. Genes with genotype-dependent variable expression levels in response to ER stress were enriched for canonical ER stress functions, such as protein folding and transport. These variable effects of genetic variation are driven by unique sets of regulatory variation that are only active under context-specific circumstances. The results of this study highlight the importance of including multiple environments and genetic backgrounds when studying the ER stress response and other cellular pathways.


2020 ◽  
Author(s):  
Giacomo Albi ◽  
Lorenzo Pareschi ◽  
Mattia Zanella

After an initial phase characterized by the introduction of timely and drastic containment measures aimed at stopping the epidemic contagion from SARS-CoV2, many governments are preparing to relax such measures in the face of a severe economic crisis caused by lockdowns. Assessing the impact of such openings in relation to the risk of a resumption of the spread of the disease is an extremely difficult problem due to the many unknowns concerning the actual number of people infected, the actual reproduction number and infection fatality rate of the disease. In this work, starting from a compartmental model with a social structure, we derive models with multiple feedback controls depending on the social activities that allow to assess the impact of a selective relaxation of the containment measures in the presence of uncertain data. Specific contact patterns in the home, work, school and other locations for all countries considered have been used. Results from different scenarios in some of the major countries where the epidemic is ongoing, including Germany, France, Italy, Spain, the United Kingdom and the United States, are presented and discussed.


Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 508-515 ◽  
Author(s):  
PJ Chenaille ◽  
SA Steward ◽  
RA Ashmun ◽  
CW Jackson

Abstract Rodents treated with 150 mg/kg of 5-fluorouracil (5-FU) exhibit a marked and prolonged rebound thrombocytosis, suggesting that feedback control of one or more megakaryocyte characteristics (size, polyploidy, or concentration) is altered. To determine the changes in megakaryocytes that lead to such a profound thrombocytosis, C3H mice were injected with 150 mg/kg 5-FU, and platelet and megakaryocyte responses were examined at frequent intervals from days 1 through 25. After 5-FU injection, all megakaryocyte indices decreased, as did platelet number. However, the decrease in platelets to one third of control was greater than the decreases in megakaryocyte indices, suggesting that thrombocytopoiesis was ineffective from days 3 through 7 post 5-FU. Megakaryocyte size began to recover on day 4, followed by polyploid DNA content on day 5, and megakaryocyte concentration and platelets at 7.5 days. Megakaryocyte size peaked on days 6 through 8 (1.25 x normal), followed by megakaryocyte polyploid DNA content on day 8, megakaryocyte concentration on days 9 through 12 (2 1/2 to 3x normal), and platelets on days 12 through 15 (2x normal). Platelet levels are thought to be important in the feedback regulation of megakaryocytes; however, only polyploid DNA content distributions showed a close inverse relationship to platelet counts during both the recovery and rebound thrombocytosis phases after 5-FU. In contrast, megakaryocyte size peaked before platelet recovery commenced, while megakaryocyte concentration increased in parallel with platelets from 7.5 to 10 days post 5-FU and continued to be maintained at 2 to 3 times normal through day 13, despite platelet levels that were more than twice normal. Both megakaryocyte size and polyploid DNA content distributions shifted toward lower values in response to the rebound thrombocytosis (DNA content on day 10 and size on days 12 and 13). Splenectomy did not substantially alter the pattern of post 5-FU rebound thrombocytosis or megakaryocyte response from that seen in intact mice, indicating that splenic megakaryocytes are not responsible for the prolonged thrombocytosis seen after this drug. In summary, the prolonged thrombocytosis after 5-FU administration results from failure to down-regulate the number of precursors entering the differentiating megakaryocyte compartment. These data indicate that megakaryocyte size and DNA content are responsive to different feedback controls than megakaryocyte concentration in this model system.


2019 ◽  
Vol 11 (10) ◽  
pp. 2931 ◽  
Author(s):  
Daniel Feldmeyer ◽  
Daniela Wilden ◽  
Christian Kind ◽  
Theresa Kaiser ◽  
Rüdiger Goldschmidt ◽  
...  

In the face of accelerating climate change, urbanization and the need to adapt to these changes, the concept of resilience as an interdisciplinary and positive approach has gained increasing attention over the last decade. However, measuring resilience and monitoring adaptation efforts have received only limited attention from science and practice so far. Thus, this paper aims to provide an indicator set to measure urban climate resilience and monitor adaptation activities. In order to develop this indicator set, a four-step mixed method approach was implemented: (1) based on a literature review, relevant resilience indicators were selected, (2) researchers, consultants and city representatives were then invited to evaluate those indicators in an online survey before the remaining indicator candidates were validated in a workshop (3) and finally reviewed by sector experts (4). This thorough process resulted in 24 indicators distributed over 24 action fields based on secondary data. The participatory approach allowed the research team to take into account the complexity and interdisciplinarity nature of the topic, as well as place- and context-specific parameters. However, it also showed that in order to conduct a holistic assessment of urban climate resilience, a purely quantitative, indicator-based approach is not sufficient, and additional qualitative information is needed.


Physiology ◽  
2007 ◽  
Vol 22 (2) ◽  
pp. 131-144 ◽  
Author(s):  
Fabio Mammano ◽  
Mario Bortolozzi ◽  
Saida Ortolano ◽  
Fabio Anselmi

The inner ear contains delicate sensory receptors that have adapted to detect the minutest mechanical disturbances. Ca2+ ions are implicated in all steps of the transduction process, as well as in its regulation by an impressive ensemble of finely tuned feedback control mechanisms. Recent studies have unveiled some of the key players, but things do not sound quite right yet.


2017 ◽  
Vol 27 (3) ◽  
pp. 199-206 ◽  
Author(s):  
Suzanne Grant ◽  
Bruce Guthrie

BackgroundPrescribing is a high-volume primary care routine where both speed and attention to detail are required. One approach to examining how organisations approach quality and safety in the face of high workloads is Hollnagel’s Efficiency and Thoroughness Trade-Off (ETTO). Hollnagel argues that safety is aligned with thoroughness and that a choice is required between efficiency and thoroughness as it is not usually possible to maximise both. This study aimed to ethnographically examine the efficiency and thoroughness trade-offs made by different UK general practices in the achievement of prescribing safety.MethodsNon-participant observation was conducted of prescribing routines across eight purposively sampled UK general practices. Sixty-two semistructured interviews were also conducted with key practice staff alongside the analysis of relevant practice documents.ResultsThe eight practices in this study adopted different context-specific approaches to safely handling prescription requests by variably prioritising speed of processing by receptionists (efficiency) or general practitioner (GP) clinical judgement (thoroughness). While it was not possible to maximise both at the same time, practices situated themselves at various points on an efficiency-thoroughness spectrum where one approach was prioritised at particular stages of the routine. Both approaches carried strengths and risks, with thoroughness-focused approaches considered safer but more challenging to implement in practice due to GP workload issues. Most practices adopting efficiency-focused approaches did so out of necessity as a result of their high workload due to their patient population (eg, older, socioeconomically deprived).ConclusionsHollnagel’s ETTO presents a useful way for healthcare organisations to optimise their own high-volume processes through reflection on where they currently prioritise efficiency and thoroughness, the stages that are particularly risky and improved ways of balancing competing priorities.


2000 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Dan Liang ◽  
Alfredo Dominguez-Rosales ◽  
Amer A. Beg ◽  
...  

A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-β (TGF-β) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor κB (NF-κB/RelA) is necessary for the inhibition of TGF-β-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-α (TNF-α). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-β receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-β/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-κB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-α and interleukin-1β (IL-1β, NF-κB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-β/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-κB/RelA.


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