scholarly journals Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 378
Author(s):  
Apparao Peddapalli ◽  
Manish Gehani ◽  
Arunasree M. Kalle ◽  
Siva R. Peddapalli ◽  
Angela E. Peter ◽  
...  
Keyword(s):  
Immune Response ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Common Pathway ◽  
Downstream Effectors ◽  
Tnf Α ◽  
Normal Human ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27 October 2020, irrespective of type of article, country, or region. Joanna Briggs Institute’s design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1β, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

scholarly journals A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA

2000 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Dan Liang ◽  
Alfredo Dominguez-Rosales ◽  
Amer A. Beg ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Transcriptional Responses ◽  
Smad Signaling ◽  
Antisense Mrna ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

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.

IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-α production in macrophages

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4123-4129 ◽  
Author(s):  
Hirotaka Kuwata ◽  
Yasuyuki Watanabe ◽  
Hiroyuki Miyoshi ◽  
Masahiro Yamamoto ◽  
Tsuneyasu Kaisho ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Lentiviral Vector ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Inducible Gene

Abstract Interleukin-10 (IL-10) plays an important role in prevention of chronic inflammation in vivo. However, the molecular mechanism by which IL-10 exerts its anti-inflammatory response is poorly understood. Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages. Lentiviral vector-mediated expression of Bcl-3 inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor α (TNF-α), but not IL-6, in macrophages. In Bcl-3-transduced and IL-10-pretreated macrophages, LPS-induced nuclear translocation of nuclear factor κB (NF-κB) p65 was not impaired. However, DNA binding by NF-κB p50/p65 was profoundly inhibited. Nuclear localization of Bcl-3 was associated with inhibition of LPS-induced TNF-α production. Overexpression of Bcl-3 suppressed activation of the TNF-α promoter, but not the IL-6 promoter. Bcl-3 interacted with NF-κB p50 and was recruited to the TNF-α promoter, but not the IL-6 promoter, indicating that Bcl-3 facilitates p50-mediated inhibition of TNF-α expression. Furthermore, Bcl-3-deficient macrophages showed defective IL-10-mediated suppression of LPS induction of TNF-α, but not IL-6. These findings suggest that IL-10-induced Bcl-3 is required for suppression of TNF-α production in macrophages. (Blood. 2003; 102:4123-4129)

Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α

2002 ◽  
Vol 282 (2) ◽  
pp. G257-G266 ◽  
Author(s):  
Hailing Liu ◽  
Brett E. Jones ◽  
Cynthia Bradham ◽  
Mark J. Czaja
Keyword(s):  
Cell Death ◽  
Oxidant Stress ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Tnf Α ◽  
Cyp2e1 Expression ◽  
Factor Α ◽  
Jnk Activation ◽  
Cytochrome P 450 ◽  
Necrosis Factor

The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-α (TNF-α)-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-α death. TNF-α treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-α response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-κB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-α-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-α stimulation. Sensitization to TNF-α-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-α toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-α toxicity in liver disease.

scholarly journals Myosin motor Myo1c and its receptor NEMO/IKK-γ promote TNF-α–induced serine307 phosphorylation of IRS-1

2006 ◽  
Vol 173 (5) ◽  
pp. 665-671 ◽  
Author(s):  
Yoshitaka Nakamori ◽  
Masahiro Emoto ◽  
Naofumi Fukuda ◽  
Akihiko Taguchi ◽  
Shigeru Okuya ◽  
...  
Keyword(s):  
Motor Protein ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Cytoskeletal Network ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Ikk Complex ◽  
Factor Α ◽  
And Function ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) signaling through the IκB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor κB essential modulator (NEMO)/IKK-γ subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-α– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-α–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-β–binding domain or silencing NEMO blocked the TNF-α signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-α–induced insulin resistance.

scholarly journals Autophagy Modulation in Lymphocytes From COVID-19 Patients: New Therapeutic Target in SARS-COV-2 Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Marta Vomero ◽  
Cristiana Barbati ◽  
Tania Colasanti ◽  
Alessandra Ida Celia ◽  
Mariangela Speziali ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Degradation Pathway ◽  
The Novel ◽  
Lysosomal Degradation ◽  
Tnf Α ◽  
Evolutionarily Conserved ◽  
Novel Coronavirus ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the novel coronavirus, causing coronavirus disease 2019 (COVID-19). During virus infection, several pro-inflammatory cytokines are produced, leading to the “cytokine storm.” Among these, interleukin (IL)-6, tumor necrosis factor‐α (TNF‐α), and IL-1β seem to have a central role in the progression and exacerbation of the disease, leading to the recruitment of immune cells to infection sites. Autophagy is an evolutionarily conserved lysosomal degradation pathway involved in different aspects of lymphocytes functionality. The involvement of IL-6, TNF‐α, and IL-1β in autophagy modulation has recently been demonstrated. Moreover, preliminary studies showed that SARS-CoV-2 could infect lymphocytes, playing a role in the modulation of autophagy. Several anti-rheumatic drugs, now proposed for the treatment of COVID-19, could modulate autophagy in lymphocytes, highlighting the therapeutic potential of targeting autophagy in SARS-CoV-2 infection.

scholarly journals Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice

2009 ◽  
Vol 296 (6) ◽  
pp. H1850-H1858 ◽  
Author(s):  
Jiyeon Yang ◽  
Yoonjung Park ◽  
Hanrui Zhang ◽  
Xiangbin Xu ◽  
Glen A. Laine ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Expression ◽  
Sodium Nitroprusside ◽  
Protein Modification ◽  
Nuclear Factor Κb ◽  
Diabetic Mice ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

We hypothesized that the interaction between tumor necrosis factor-α (TNF-α)/nuclear factor-κB (NF-κB) via the activation of IKK-β may amplify one another, resulting in the evolution of vascular disease and insulin resistance associated with diabetes. To test this hypothesis, endothelium-dependent (ACh) and -independent (sodium nitroprusside) vasodilation of isolated, pressurized coronary arterioles from mLepr db (heterozygote, normal), Lepr db (homozygote, diabetic), and Lepr db mice null for TNF-α ( dbTNF−/ dbTNF−) were examined. Although the dilation of vessels to sodium nitroprusside was not different between Lepr db and mLepr db mice, the dilation to ACh was reduced in Lepr db mice. The NF-κB antagonist MG-132 or the IKK-β inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in Lepr db mice, but the responses in mLepr db mice were unaffected. The protein expression of IKK-α and IKK-β were higher in Lepr db than in mLepr db mice; the expression of IKK-β, but not the expression of IKK-α, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF-α in diabetic mice. Lepr db mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF-α and NF-κB and the protein modification of phosphorylated (p)-IKK-β and p-JNK were greater in Lepr db mice, but NaSal attenuated TNF-α, NF-κB, p-IKK-β, and p-JNK in Lepr db mice. The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Lepr db compared with mLepr db mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Lepr db mice. MG-132 or the neutralization of TNF-α reduced superoxide production in Lepr db mice. In conclusion, our results indicate that the interaction between NF-κB and TNF-α signaling induces the activation of IKK-β and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.

scholarly journals Berry Phenolic and Volatile Extracts Inhibit Pro-Inflammatory Cytokine Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB Signaling Pathway

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 871
Author(s):  
Inah Gu ◽  
Cindi Brownmiller ◽  
Nathan B. Stebbins ◽  
Andy Mauromoustakos ◽  
Luke Howard ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Complex Mixture ◽  
Limited Information ◽  
Potential Health ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Raw264.7 Macrophage ◽  
Necrosis Factor

Berries are a rich source of phytochemicals, especially phenolics well known for protective activity against many chronic diseases. Berries also contain a complex mixture of volatile compounds that are responsible for the unique aromas of berries. However, there is very limited information on the composition and potential health benefits of berry volatiles. In this study, we isolated phenolic and volatile fractions from six common berries and characterized them by HPLC/HPLC-MS and GC/GC-MS, respectively. Berry phenolic and volatile fractions were evaluated for an anti-inflammatory effect using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells by measuring levels of pro-inflammatory cytokines and the nuclear factor-kappa B (NF-κB) signaling pathway. Results showed that LPS-induced excessive production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which were inhibited by berry phenolic and volatile extracts. Moreover, berry phenolic and volatile extracts reduced the nuclear translocation of NF-κB by blocking the phosphorylation of p65 and degradation of IκBα. These findings showed that berry volatiles from six berries had comparable anti-inflammatory effects to berry phenolics through the suppression of pro-inflammatory mediators and cytokines expression via NF-κB down-regulation, despite being present in the fruit at a lower concentration.

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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