Nuclear Factor-κB–Dependent Induction of Interleukin-8 Gene Expression by Tumor Necrosis Factor : Evidence for an Antioxidant Sensitive Activating Pathway Distinct From Nuclear Translocation

Vlahopoulos, Spiros; Boldogh, István; Casola, Antonella; Brasier, Allan R.

doi:10.1182/blood.v94.6.1878

Cited by 216 publications

(96 citation statements)

References 44 publications

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“…It is well-established that calpain and proteasome pathways mediate cytoplasmic proteolysis of IκB inhibitors to release NFκB from cytoplasmic stores [26], resulting in exposure of nuclear localization sequences promoting efficient translocation of NFκB into the nucleus. However, we made the seminal observation that nuclear translocation alone is insufficient to activate innate NFκB-dependent networks [27,28]. The mechanism underlying viral induced NFκB activation is via the production of reactive oxygen species (ROS)-induced nuclear damage.…”

Section: The Airway Epithelial Cell As a Sensor Of Rsv Replicationmentioning

confidence: 99%

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Brasier

2020

Viruses

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Respiratory syncytial virus infection is responsible for seasonal upper and lower respiratory tract infections worldwide, causing substantial morbidity. Self-inoculation of the virus into the nasopharynx results in epithelial replication and distal spread into the lower respiratory tract. Here, respiratory syncytial virus (RSV) activates sentinel cells important in the host inflammatory response, resulting in epithelial-derived cytokine and interferon (IFN) expression resulting in neutrophilia, whose intensity is associated with disease severity. I will synthesize key findings describing how RSV replication activates intracellular NFκB and IRF signaling cascades controlling the innate immune response (IIR). Recent studies have implicated a central role for Scg1a1 + expressing progenitor cells in IIR, a cell type uniquely primed to induce neutrophilic-, T helper 2 (Th2)-polarizing-, and fibrogenic cytokines that play distinct roles in disease pathogenesis. Molecular studies have linked the positive transcriptional elongation factor-b (P-TEFb), a pleiotrophic chromatin remodeling complex in immediate-early IIR gene expression. Through intrinsic kinase activity of cyclin dependent kinase (CDK) 9 and atypical histone acetyl transferase activity of bromodomain containing protein 4 (BRD4), P-TEFb mediates transcriptional elongation of IIR genes. Unbiased proteomic studies show that the CDK9•BRD4 complex is dynamically reconfigured by the innate response and targets TGFβ-dependent fibrogenic gene networks. Chronic activation of CDK9•BRD4 mediates chromatin remodeling fibrogenic gene networks that cause epithelial mesenchymal transition (EMT). Mesenchymal transitioned epithelial cells elaborate TGFβ and IL6 that function in a paracrine manner to expand the population of subepithelial myofibroblasts. These findings may account for the long-term reduction in pulmonary function in children with severe lower respiratory tract infection (LRTI). Modifying chromatin remodeling properties of the CDK9•BRD4 coactivators may provide a mechanism for reducing post-infectious airway remodeling that are a consequence of severe RSV LRTIs.Viruses 2020, 12, 472 2 of 17 spread into the lower airways produces lower respiratory tract infection (LRTI), whose clinical features include bronchiolitis and pneumonia. Pathologically, LRTI is associated with epithelial giant cell formation, necrosis, sloughing, producing mucous plugging, ventilation-perfusion mismatching, and acute hypoxic respiratory failure [2][3][4]. The findings that the initial clinical manifestations of hypoxia are correlated with high viral titers and epithelial-derived cytokines [5,6] indicates that RSV activation of the IIR plays an important component of early disease manifestations.Observational studies of naturally occurring RSV infections in humans suggest that acute infection produces an initial neutrophilic airway inflammation [7], followed by a CD8+ T-cell response important in viral clearance (reviewed in [8]). Because protective IgA antibodies wane six months after...

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Section: The Airway Epithelial Cell As a Sensor Of Rsv Replicationmentioning

confidence: 99%

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Brasier

2020

Viruses

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“…Tumour necrosis factor‐ α (TNF‐ α ) is a major factor in the development of chronic inflammatory conditions (Maini & Taylor, 2000). This cytokine elicits a wide spectrum of cellular responses including leukocyte adhesion and migration as well as activation of inflammatory cells, with enhanced secretion of additional mediators such as interleukin‐1 and interleukin‐8 (Vassalli, 1992; Vlahopoulos et al ., 1999).…”

Section: Introductionmentioning

confidence: 99%

Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor‐α by inhibiting nuclear factor‐κB activation

Posadas

Rosa

Terencio

et al. 2003

British J Pharmacology

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1 The marine product cacospongionolide B, a sesterterpene isolated from the Mediterranean sponge Fasciospongia cavernosa, is an inhibitor of secretory phospholipase A 2 with anti-inflammatory properties. In this work, we have studied the mechanism of action of this compound in the inflammatory response induced by zymosan in primary cells and in the mouse air pouch. 2 In mouse peritoneal macrophages, cacospongionolide B was able to downregulate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), resulting in decreased production of NO and prostaglandin E 2 (PGE 2 ). This compound also reduced tumour necrosis factora (TNF-a) mRNA expression and TNF-a levels. 3 Cacospongionolide B inhibited nuclear factor-kB (NF-kB)-DNA binding activity and the nuclear translocation of this transcription factor. 4 Treatment of cells with cacospongionolide B impaired NF-kB inhibitory protein (IkB-a) phosphorylation and enhanced IkB-a expression. 5 Inhibition of iNOS, COX-2 and inflammatory mediators was confirmed in the mouse air pouch. 6 These results show that cacospongionolide B is able to control NO, PGE 2 and TNF-a production in vitro and in vivo, effects likely dependent on NF-kB inhibition.

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“…We found that IFN‐β was increasingly expressed 1 day after infection and kept increasing in the time observed and was thought to have immune adjuvant effect in corneal infection. TNF‐α has been proved to be a kind of apoptosis‐inducing cytokines and may play the same role in this process, which resulted in the tissue (34).…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor 4 signalling pathway activation in a rat model of Acanthamoeba Keratitis

Ren

2010

Parasite Immunology

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The pathogenesis of Acanthamoeba keratitis (AK) is complicated. In our previous studies, TLR4 was found involved in the process of infection by Acanthamoeba in human corneal cells. The purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) signalling pathway in Wistar rats challenged with Acanthamoeba. The rat model of AK was established. Corneas were collected and analysed by real-time PCR to assess the mRNA levels of TLR 2, 4, myeloid differentiation protein (MyD)88, nuclear factor (NF)-κB, extracellular signal-regulated kinase (ERK), interleukin (IL)-8, tumour necrosis factor (TNF)-α and interferon (IFN) -β. Immunocytochemistry and Western blot were conducted to examine the proteins of TLR2, TLR4, p-Erk1/2 and p-IκB. Specific inhibitors PDTC and U0126 were used to pretreat the animals to determine the exact receptor and signalling pathway involved in pathogenesis. Expressions of TLR4, MyD88, all three cytokines, NF-κB, p-IκB and p-Erk1/2 were increased in Acanthamoeba-treated rat corneas. PDTC inhibited the production of IL-8 and TNF-α, while U0126 inhibited the synthesis of IFN-β. TLR4 was involved in sensing the challenge of Acanthamoeba and inducing production of cytokines through TLR4-NF-κB and TLR4-Erk1/2 pathways in corneas of Wistar rats.

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Nuclear Factor-κB–Dependent Induction of Interleukin-8 Gene Expression by Tumor Necrosis Factor : Evidence for an Antioxidant Sensitive Activating Pathway Distinct From Nuclear Translocation

Cited by 216 publications

References 44 publications

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor‐α by inhibiting nuclear factor‐κB activation

Toll‐like receptor 4 signalling pathway activation in a rat model of Acanthamoeba Keratitis

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