scholarly journals HMGB1 translocation and release mediate cigarette smoke–induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway

2017 ◽  
Vol 28 (1) ◽  
pp. 201-209 ◽  
Author(s):  
Yao Cheng ◽  
Dan Wang ◽  
Bin Wang ◽  
Huanan Li ◽  
Junjie Xiong ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Cigarette Smoke ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Pulmonary Inflammation ◽  
High Mobility ◽  
Lung Epithelial Cells ◽  
Proinflammatory Cytokine Production ◽  
Tnf Α

We performed studies to determine the role of high-mobility group box 1 (HMGB1) in cigarette smoke (CS)–induced pulmonary inflammation. After mice were exposed to five cigarettes four times a day for 3 d, toll-like receptor 4 (TLR4) expression and TLR4-mediated signaling were significantly up-regulated, and HMGB1 had translocated from the nucleus to the cytoplasm in lung epithelial cells and then been released into the extracellular lung space. On CS exposure, inflammatory cell recruitment and proinflammatory cytokine production were significantly increased in lung tissue and bronchoalveolar lavage, and these effects depended on the TLR4 signaling pathway. HMGB1 inhibition decreased the CS-induced inflammatory response, whereas treatment with exogenous HMGB1 aggravated the damage and increased the phosphorylation of JNK, p38, and IκBα in the lungs of wild-type mice but not in TLR4-knockout mice. Blockade of TLR4 action or TLR4 knockout significantly inhibited HMGB1-induced proinflammatory cytokine production in mouse tracheal epithelial (MTE) cells and lung tissues. In addition, a MyD88 deficiency inhibited JNK, p38, and IκBα phosphorylation, and this effect was associated with the suppressed production of TNF-α and IL-1β in MTE cells and lung tissues in response to CS stimulation. Thus HMGB1 activates the NF-κB and JNK/p38 pathways through TLR4/MyD88-dependent signaling and induces an inflammatory response in lungs exposed to CS.

scholarly journals Human Cytomegalovirus MicroRNAs miR-US5-1 and miR-UL112-3p Block Proinflammatory Cytokine Production in Response to NF-κB-Activating Factors through Direct Downregulation of IKKα and IKKβ

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Meaghan H. Hancock ◽  
Lauren M. Hook ◽  
Jennifer Mitchell ◽  
Jay A. Nelson
Keyword(s):  
Human Cytomegalovirus ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Hcmv Infection ◽  
Cytokine Production ◽  
Lytic Infection ◽  
Wild Type Virus ◽  
Proinflammatory Cytokine Production ◽  
Iκb Kinase ◽  
Tnf Α

ABSTRACTEmerging evidence indicates that human cytomegalovirus (HCMV) manipulates host cell signaling pathways using both proteins and noncoding RNAs. Several studies have shown that HCMV induces NF-κB signaling early in infection, resulting in the induction of antiviral proinflammatory cytokines with a subsequent reduction of these cytokines late in infection. The mechanism for late cytokine reduction is unknown. In this study, we show that HCMV microRNAs (miRNAs) miR-US5-1 and miR-UL112-3p target the IκB kinase (IKK) complex components IKKα and IKKβ to limit production of proinflammatory cytokines in response to interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α). Transfection of miR-UL112-3p and miR-US5-1 mimics reduced endogenous IKKα and IKKβ protein levels, and site-directed mutagenesis of the 3′ untranslated regions (UTRs) identified the binding sites for each miRNA. Infection with mutant viruses lacking these miRNAs resulted in increased levels of IKKα and IKKβ proteins, an impaired ability to control NF-κB signaling at late times of lytic infection, and increased production of proinflammatory cytokines compared to wild-type virus in cell types relevant to HCMV infectionin vivo. These phenotypes were rescued by preexpression of miR-US5-1 and miR-UL112-3p in infected cells or by a miR-US5-1/miR-UL112-3p double mutant virus that expresses short hairpin RNAs (shRNAs) targeting IKKα and IKKβ, demonstrating the gene specificity of the miRNAs. These observations describe a mechanism through which HCMV miRNAs expressed late in the infectious cycle downregulate proinflammatory cytokine production to create a cellular proviral environment.IMPORTANCEHuman cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in transplant recipients and causes hearing loss and mental retardation when acquired congenitally. Initial events during HCMV infection result in the activation of NF-κB signaling, which culminates in the production of IL-6, CCL5, and TNF-α. Several viruses have developed mechanisms to block the antiviral effects of these cytokines. We show here that two HCMV miRNAs, miR-US5-1 and miR-UL112-3p, specifically downregulate IKKα and IKKβ signaling factors necessary to propagate NF-κB signaling and subsequent IL-6, CCL5, and TNF-α production. Regulation of these proinflammatory cytokines during lytic infection and during latency is critical to viral survival in the host.

scholarly journals Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages

2012 ◽  
Vol 303 (7) ◽  
pp. L608-L616 ◽  
Author(s):  
Huy A. Nguyen ◽  
Murugesan V. S. Rajaram ◽  
Douglas A. Meyer ◽  
Larry S. Schlesinger
Keyword(s):  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Protein A ◽  
Surfactant Protein ◽  
Negative Regulator ◽  
Surfactant Protein A ◽  
Proinflammatory Cytokine Production ◽  
Human Macrophages ◽  
Tnf Α

Alveolar macrophages (AMs) are exposed to frequent challenges from inhaled particulates and microbes and function as a first line of defense with a highly regulated immune response because of their unique biology as prototypic alternatively activated macrophages. Lung collectins, particularly surfactant protein A (SP-A), contribute to this activation state by fine-tuning the macrophage inflammatory response. During short-term (10 min–2 h) exposure, SP-A's regulation of human macrophage responses occurs through decreased activity of kinases required for proinflammatory cytokine production. However, AMs are continuously exposed to surfactant, and the biochemical pathways underlying long-term reduction of proinflammatory cytokine activity are not known. We investigated the molecular mechanism(s) underlying SP-A- and surfactant lipid-mediated suppression of proinflammatory cytokine production in response to Toll-like receptor (TLR) 4 (TLR4) activation over longer time periods. We found that exposure of human macrophages to SP-A for 6–24 h upregulates expression of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR-mediated NF-κB activation. Exposure to Survanta, a natural bovine lung extract lacking SP-A, also enhances IRAK-M expression, but at lower magnitude and for a shorter duration than SP-A. Surfactant-mediated upregulation of IRAK-M in macrophages suppresses TLR4-mediated TNF-α and IL-6 production in response to LPS, and IRAK-M knockdown by small interfering RNA reverses this suppression. In contrast to TNF-α and IL-6, the surfactant components upregulate LPS-mediated immunoregulatory IL-10 production, an effect reversed by IRAK-M knockdown. In conclusion, these data identify an important signaling regulator in human macrophages that is used by surfactant to control the long-term alveolar inflammatory response, i.e., enhanced IRAK-M activity.

scholarly journals Enhanced Proinflammatory Cytokine Production and Immunometabolic Impairment of NK Cells Exposed to Mycobacterium tuberculosis and Cigarette Smoke

2022 ◽  
Vol 11 ◽  
Author(s):  
Yafei Rao ◽  
Xiaoyan Gai ◽  
Yanqing Le ◽  
Jing Xiong ◽  
Yujia Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Oxidative Phosphorylation ◽  
Nk Cells ◽  
Cigarette Smoke ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Nk Cell ◽  
Proinflammatory Cytokine Production ◽  
Cell Subpopulations

AimSmoker COPD patients with chest radiological signs of prior tuberculosis (TB) showed more severe lung damage, but the mechanisms remain unclear. Emerging evidence has implicated NK cells in the pathogenesis of both COPD and TB. The purpose of this study was to delineate the profile and cytokine production of NK-cell subpopulations and their immunometabolic changes after exposure to both cigarette smoke (CS) and Mycobacterium tuberculosis(MTB).MethodsWe profiled NK-cell subpopulations in terms of percentage and cytokine production by flow cytometry in smoker patients with pulmonary TB (PTB). In an in vitro coexposure model, we investigated proinflammatory cytokine production, glycolytic influx, and oxidative phosphorylation of NK cells under CS extract (CSE) and PPD costimulation.ResultsPeripheral blood NK cells in smoker patients with active PTB (CS+PTB group) showed altered proportion of subpopulations and excessive proinflammatory cytokine expressions. In vitro, CSE- and PPD-coexposed NK-92 cells displayed enhanced proinflammatory cytokine production, concurrent with decreased glycolytic influx and oxidative phosphorylation.ConclusionSmoker patients with active PTB showed enhanced proinflammatory cytokine expression within altered NK cell subpopulations. CSE and PPD coexposure induced heightened cytokine production concurrent with impaired cell metabolism in NK cells. These novel data suggest a potential role of NK cells in the pathogenesis of lung injury in subjects with coexposure to CS and TB.

scholarly journals Macrophage-Derived Cell Lines Do Not Express Proinflammatory Cytokines after Exposure to Bacillus anthracis Lethal Toxin

2001 ◽  
Vol 69 (2) ◽  
pp. 1175-1177 ◽  
Author(s):  
James L. Erwin ◽  
Luis M. DaSilva ◽  
Sina Bavari ◽  
Stephen F. Little ◽  
Arthur M. Friedlander ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Bacillus Anthracis ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Messenger Rna ◽  
Cytokine Production ◽  
Lethal Toxin ◽  
Proinflammatory Cytokine Production ◽  
Present Evidence ◽  
Low Levels

ABSTRACT We present evidence that Bacillus anthracis lethal toxin (LT) suppresses rather than induces proinflammatory cytokine production in macrophages. Suppression is observed with extremely low levels of LT and involves inhibition of transcription of cytokine messenger RNA. Thus, LT may contribute to anthrax pathogenesis by suppressing the inflammatory response.

scholarly journals Suppression of lncRNA MALAT1 Reduces LPS- or IL-17A-Induced Inflammatory Response in Human Middle Ear Epithelial Cells via the NF-κB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xiangru Yang ◽  
Qinna Zhang ◽  
Hui Lu ◽  
Chenxin Wang ◽  
Lijun Xia
Keyword(s):  
Inflammatory Response ◽  
Western Blot ◽  
Middle Ear ◽  
Blot Analysis ◽  
Proinflammatory Cytokine ◽  
Western Blot Analysis ◽  
Cytokine Production ◽  
Proinflammatory Cytokine Production ◽  
Protein Levels ◽  
Human Middle Ear

Otitis media (OM) is a common inflammatory disease of the middle ear cavity and mainly occurs in children. As a critical regulator of inflammation response, the nuclear factor kappa B (NF-κB) pathway has been found to play an essential role in the pathogenesis of various human diseases. The aim of this study was to explore the potential mechanism under the inflammatory response of human middle ear epithelial cells (HMEECs). We established in vitro models of OM by treating HMEECs with lipopolysaccharide (LPS) or interleukin 17A (IL-17A). Enzyme-linked immunosorbent assay and western blot analysis were used to measure the inflammatory response of HMEECs under LPS or IL-17A stimulation. The results revealed that the concentrations of proinflammatory cytokines ( p < 0.001 ) and protein levels of mucin (MUC) (for MUC5AC, p = 0.002 , p = 0.004 ; for MUC8, p = 0.004 , p < 0.001 ) were significantly elevated by LPS or IL-17A stimulation in HMEECs. Moreover, we found that LPS or IL-17A treatment promoted the phosphorylation of IκBα (for p-IκBα, p = 0.018 , p = 0.002 ; for IκBα, p = 0.238 , p = 0.057 ) and the translocation of p65 from cytoplasm to nucleus in HMEECs (for nucleus p65, p = 0.01 ; for cytoplasm p65, p < 0.001 ). In addition, RT-qPCR analysis revealed that long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was verified to be upregulated in LPS- or IL-17A-stimulated HMEECs ( p < 0.001 ). Western blot analysis and immunofluorescence staining assay revealed that that MALAT1 knockdown significantly suppressed the activation of the NF-κB pathway by reducing phosphorylated IκBα levels and inhibiting the nuclear translocation of p65 ( p < 0.001 ) in LPS- or IL-17A-stimulated HMEECs (for p-IκBα, p < 0.001 ; for IκBα, p = 0.242 , p = 0.647 ). Silence of MALAT1 decreased the proinflammatory cytokine production and MUC protein levels ( p < 0.001 ). Furthermore, rescue assays revealed that the increase of proinflammatory cytokine production (for TNF-α, p = 0.002 , p = 0.015 ; for IL-1β, p < 0.001 , p = 0.006 ; for IL-6, p = 0.002 , p < 0.001 ) and MUC protein levels (for MUC5AC, p = 0.001 , p < 0.001 ; for MUC8, p < 0.001 , p = 0.001 ) induced by MALAT1 overexpression was neutralized by 4-N-[2-(4-phenoxyphenyl) ethyl] quinazoline-4, 6-diamine (QNZ) treatment in LPS- or IL-17A-stimulated HMEECs. In conclusion, MALAT1 promotes inflammatory response in LPS- or IL-17A- stimulated HMEECs via the NF-κB signaling pathway, which may provide a potential novel insight for the treatment of OM.

scholarly journals Treadmill Running Improves Spatial Learning Memory Through Inactivation of Nuclear Factor Kappa B/Mitogen-Activated Protein Kinase Signaling Pathway in Amyloid-β-Induced Alzheimer Disease Rats

2021 ◽  
Vol 25 (Suppl 1) ◽  
pp. S35-43 ◽  
Author(s):  
Sang-Hoon Kim ◽  
Young Jun Ko ◽  
Jee-Youn Kim ◽  
Young-Je Sim
Keyword(s):  
Signaling Pathway ◽  
Spatial Learning ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Amyloid Β ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Treadmill Running ◽  
Proinflammatory Cytokine Production ◽  
Spatial Learning Memory

Purpose: Exercise is known to reduce proinflammatory cytokines production and apoptosis. We investigated the effect of treadmill running on spatial learning memory in terms of activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway in Alzheimer disease (AD) rats. We also evaluated the effect of treadmill running on proinflammatory cytokine production and apoptosis.Methods: Using the stereotaxic frame, amyloid-β (Aβ) was injected into the lateral ventricle of the brain. The rats belong to treadmill running groups were forced to run on a motorized treadmill for 30 minutes per a day during 4 weeks, starting 3 days after Aβ injection. Morris water maze task was done for the determination of spatial learning memory. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry for cleaved caspase-3, and western blot for NF-κB, inhibitory protein of NF-κB (IκB), MAPK signaling pathway, tumor necrosis factor (TNF)-α, interleukin (IL)-1β were done.Results: Induction of AD increased proinflammatory cytokine secretion by activating the NF-κB/MAPK signaling pathway. These changes induced apoptosis in the hippocampus and reduced spatial learning memory. In contrast, treadmill running inactivated the NF-κB/MAPK signaling pathway and suppressed proinflammatory cytokine production. These changes inhibited apoptosis and improved spatial learning memory.Conclusions: Current results showed that treadmill running promoted spatial learning memory through suppressing proinflammatory cytokine production and apoptosis via inactivation of NF-κB/MAPK signaling pathway. Treadmill exercise can be considered an effective intervention for symptom relieve of AD.

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