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The activation of transcription factor NF-kappaB is controlled by two main pathways: the classical canonical (RelA/p65-p50)- and the alternative noncanonical (RelB/p52)-NF-kappaB pathways. RelB has been shown to play a protective role in RelA/p65-mediated proinflammatory cytokine release in immune-inflammatory lymphoid cells. Increased infiltration...
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Grb2 (growth-factor receptor-bound protein-2) is a signaling adaptor that interacts with numerous receptors and intracellular signaling molecules. However, its role in B-cell development and function remains unknown. Here we show that ablation of Grb2 in B cells results in enhanced B-cell receptor signaling; however, mutant B cells do not form germ...
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... Macrophages isolated from BALF collected from patients with PH also displayed activated NF-κB [118]. This was further supported in an in vivo COPD model where CS increased NF-κB signaling activity and its subsequent nuclear recruitment to the promoters of several inflammatory genes [63,117,119]. ...
Inflammatory signaling is a major component in the development and progression of many lung diseases, including asthma, chronic obstructive pulmonary disorder (COPD), and pulmonary hypertension (PH). This chapter will provide a brief overview of asthma, COPD, and PH and how inflammation plays a vital role in these diseases. Specifically, we will discuss the role of reactive oxygen species (ROS) and Ca2+ signaling in inflammatory cellular responses and how these interactive signaling pathways mediate the development of asthma, COPD, and PH. We will also deliberate the key cellular responses of pulmonary arterial (PA) smooth muscle cells (SMCs) and airway SMCs (ASMCs) in these devastating lung diseases. The analysis of the importance of inflammation will shed light on the key questions remaining in this field and highlight molecular targets that are worth exploring. The crucial findings will not only demonstrate the novel roles of essential signaling molecules such as Rieske iron-sulfur protein and ryanodine receptor in the development and progress of asthma, COPD, and PH but also offer advanced insight for creating more effective and new therapeutic targets for these devastating inflammatory lung diseases.
... The activation of NF-κB occurs when it dissociates from IκBα, as the negative regulator for NF-κB, which is degraded in the process. NF-κB phosphorylation involves IκBα activation, which is catalyzed by IKK (38). Liberation from IκB promotes NF-κB to translocate into the nucleus. ...
Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensitized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA.
... In brief, Kentucky 3R4F research-reference filtered CSEs were bubbled for 1-2 min through 10 ml serum-free DMEM/F12 supplemented with 1% penicillin-streptomycin with a peristaltic vacuum pump. Next, the solution containing smoke was filtered through a 0.22-mm filter to remove large particles and was regarded as a 10% CSE solution (30). CSE was prepared within 30 min and stored at 280°C for additional experiments. ...
The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2(+/+), but not in Nrf2(-/-) mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling.
... NF-kB is extremely important in the induction of inflammatory responses in the lung as reported in mice lacking NF-kB signaling, where the attenuation of inflammation, decreased inflammatory cytokines, and serum IgE levels were observed (Poynter et al., 2004). CS can modulate NF-kB signaling probably inducing the ubiquitination and subsequent proteasomal degradation of IkB (Hasnis et al., 2007; Yang et al., 2009b). Similarly, CS-derived ROS potentially induce NF-kB activation through several distinct mechanisms requiring either IkB phosphorylation/degradation or phosphorylation/dissociation . ...
First-hand and second-hand tobacco smoke are causally linked to a huge number of deaths and are responsible for a broad spectrum of pathologies such as cancer, cardiovascular, respiratory, and eye diseases as well as adverse effects on female reproductive function. Cigarette smoke is a complex mixture of thousands of different chemical species, which exert their negative effects on macromolecules and biochemical pathways, both directly and indirectly. Many compounds can act as oxidants, pro-inflammatory agents, carcinogens, or a combination of these. The redox behavior of cigarette smoke has many implications for smoke related diseases. Reactive oxygen and nitrogen species (both radicals and non-radicals), reactive carbonyl compounds, and other species may induce oxidative damage in almost all the biological macromolecules, compromising their structure and/or function. Different quantitative and redox proteomic approaches have been applied in vitro and in vivo to evaluate, respectively, changes in protein expression and specific oxidative protein modifications induced by exposure to cigarette smoke and are overviewed in this review. Many gel-based and gel-free proteomic techniques have already been used successfully to obtain clues about smoke effects on different proteins in cell cultures, animal models, and humans. The further implementation with other sensitive screening techniques could be useful to integrate the comprehension of cigarette smoke effects on human health. In particular, the redox proteomic approach may also help identify biomarkers of exposure to tobacco smoke useful for preventing these effects or potentially predictive of the onset and/or progression of smoking-induced diseases as well as potential targets for therapeutic strategies. © 2013 Wiley Periodicals, Inc. Mass Spec Rev.
... The lung is a direct target for oxidative injury from reactive oxygen species (ROS) and free radicals. Oxidative stress results in increased cellular signaling associated with posttranslational modifications of histones and nonhistone proteins, and redox modifications of proteins implicated in chromatin remodeling (48,152,179,181) (Fig. 1). ...
... Based on the redox status of the cells, members of the MAPK family are activated, leading to a multifaceted transactivation of redox-sensitive transcription factors (ATF-2, CBP) (6,147). Furthermore, activation of upstream kinases, such as nuclear factor-jB (NF-jB)-inducing kinase, mitogenand stress-activated kinase 1, and IjB kinase-a, results in downstream chromatin remodeling events that alter the function of various gene promoters (27,28,138,179,181). This epigenetic mechanism modulates a series of specific proinflammatory gene transcription events that modulate apoptosis, autophagy, senescence, proliferation, transformation, and differentiation (53). ...
Significance:
Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance.
Recent advances:
Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress.
Critical issues:
Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress.
Future directions:
Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.
... Our ChIP analysis revealed that MSK1, and its substrates RelA/p65 (Ser276), acetylated histone H3 (Lys9) and histone H4 (Lys12) are recruited to the promoters of pro-inflammatory genes in response to CS in epithelial cells. This is similar to the findings that CS causes recruitment of IKKα and RelA/p65 to the promoters of pro-inflammatory genes, such as MIP-2 and IL-6 in mouse lung [10], [31]. Earlier study by Gilmour et al. demonstrated a role of histone H4 acetylation in regulation of IL-8 gene expression using the ChIP assay showing an increased association of acetylated H4 on IL-8 gene promoter following TSA, PM10, and TNF treatments after 24 h [64]. ...
... We and others have demonstrated the role of the NF-κB signaling pathway in pro-inflammatory gene transcription and chromatin modifications [1], [2], [10], [28], [29], [30]. Studies in the past have shown that NF-κB is recruited to the promoter of pro-inflammatory genes in CS-exposed rodent lungs, resulting in increased histone acetylation [10], [31], [32], [33]. ...
Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD.
... The dominant negative (DN)-NIK plasmid with NIK mutant domain on K429 and K430 (K429/430A) was obtained as described previously [29,30]. Mock-transfected cells were used as control. ...
Nuclear factor (NF)-κB inducing kinase (NIK) is a central player in the non-canonical NF κB pathway, which phosphorylates IκB kinase α (IKKα) resulting in enhancement of target gene expression. We have recently shown that IKKα responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-κB activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFα with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFα increase NIK levels causing phosphorylation of IKKα, which leads to histone acetylation.
To test this hypothesis, we investigated whether NIK mediates effects of CS and TNFα on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKα/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFα. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFα-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKβ/NF-κB pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs.
Overall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.
... However, the pathways responsible for abnormal antibody production form B-cells in response to cigarette smoke are not known. We have recently showed that decreased RelB in B-cells in response to cigarette smoke would be the key in signaling for altered antibody production (Yang et al., 2009). ...
... The alternative or noncanonical pathway requires the NF-κB-inducing kinase (NIK), which cooperates with IKK-α to induce the processing of the p100 C-terminus (termed IκBδ), which results in the nuclear translocation of p52:RelB (Senftleben et al., 2001;Yin et al., 2001;Xiao et al., 2004). Cigarette smoke exposure increased the levels of p52, RelB, IKK-α and NIK as well as RelB interaction of p52 with NIK in mouse lung (Yang et al., 2008;Yang et al., 2009). This was associated with recruitment of RelB on the promoter of pro-inflammatory genes suggesting that alternative NF-κB pathway also participates in cigarette smoke-mediated lung inflammatory response (Yang et al., 2008). ...
... As another component of NF-κB pathway, RelB was also recruited on proinflammatory genes promoters via NIK and/or IKK-α activation by cigarette smoke in MonoMac6 cells. However, it is interesting to note that RelB was degraded rapidly by proteolysis in B lymphocytes in response to cigarette smoke suggesting RelB is differentially regulated by cigarette smoke in cell specific manner and speculating the proand anti-inflammatory protective role of RelB which is cell type-specific (Yang et al., 2009). Furthermore, RelB degradation in B cells may signal for RelA/p65 activation leading to proinflammatory cytokines release, and/or alter the acquired immunity resulting in abnormal/self antibody production. ...
Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD.
... There are several evidences showing increased gene transcription that leads to increase in histone acetylation , and histone hypoacetylation which is further linked to decreased gene transcription (Kuo and Allis, 1998; Wolffe, 1997; Workman and Kingston, 1998). A variety of stimuli in air such as airborne particulate matter with a diameter of <10 mm diameter (PM 10 ) and cigarette smoke (CS), which are associated with chronic lung and cardiovascular diseases, increased histone acetylation by reactive oxygen species (ROS), and redox modifications of proteins involved in chromatin remodeling in lung epithelial cells, human monocytes/macrophages, and mouse lungs (Gilmour et al., 2003; Tomita et al., 2003; Yang et al., , 2009 ). Furthermore, histone acetylation and deacetylation , and SIRT1 are linked to cell-cycle progression, DNA repair, and recombination events as well as inflammatory gene transcription which can be affected by redox signaling (Kouzarides, 1999; Taplick et al., 1998). ...
... With the development of antibodies for specific lysine residues in histones such as H3K9, H3K14, H3K18, H3K27, H4K5, H4K8, H4K12, and H4K16, specific histone acetylation assay is now possible by Western blotting (Yang et al., , 2009). Histone protein in cells or tissues is extracted as mentioned in histone extraction procedure. ...
... Using this approach, the in vivo DNA binding site of any protein can be detected. Here, we describe the stepwise protocol (Fig. 13.1 ) currently used to immunoprecipitate the formaldehyde cross-linked chromatin and further analyze the immunoprecipitated DNA by semiquantitative PCR (Yan et al., 2004; Yang et al., , 2009). This technique is elegantly described by several investigators (Ooi and Wood, 2009; Weinmann, 2004; Yan et al., 2004). ...
Epigenetics is referred to as heritable changes in gene expression but not encoded in the DNA sequence itself which occurs during posttranslational modifications in DNA and histones. These epigenetic modifications include histone acetylation, deacetylation, and methylation. Acetylation by histone acetyltransferases (HATs) of specific lysine residues on the N-terminal tail of core histones results in uncoiling of the DNA and increased accessibility to transcription factor binding. In contrast, histone deacetylation by histone deacetylases (HDACs) represses gene transcription by promoting DNA winding thereby limiting access to transcription factors. Reactive oxygen species (ROS) are involved in cellular redox alterations, such as amplification of proinflammatory and immunological responses, signaling pathways, activation of transcription factors (NF-kappaB and AP-1), chromatin remodeling (histone acetylation and deacetylation), histone/protein deacetylation by sirtuin 1 (SIRT1) and gene expression. The glutathione redox status plays an important role in protein modifications and signaling pathways, including effects on redox-sensitive transcription factors. Protein S-glutathiolation and mixed disulfide formation as candidate mechanisms for protein regulation during intracellular oxidative stress have gained a renewed impetus in view of their involvements in redox regulation of signaling proteins. A variety of methods are applied to study the epigenetic processes to elucidate the molecular mysteries underlying epigenetic inheritance. These include chromatin immunoprecipitation (ChIP), which is a powerful tool to study protein-DNA interaction and is widely used in many fields to study protein associated with chromatin, such as histone and its isoforms and transcription factors, across a defined DNA domain. Here, we describe some of the contemporary methods used to study oxidative stress and thiol redox signaling involved in epigenetic (histone acetylation, deacetylation, and methylation) and chromatin remodeling (HAT, HDAC, SIRT1) research.
Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 μg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.
