Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent Mechanism

Lora, José M.; Zhang, Dong Mei; Liao, Sha; Burwell, Timothy; King, Anne M.; Barker, Philip A.; Singh, L. P.; Keaveney, Marie; Morgenstern, Jay P.; Gutierrez-Ramos, José-Carlos; Coyle, Anthony J.; Fraser, Christopher C.

doi:10.1074/jbc.m507977200

Cited by 88 publications

(65 citation statements)

References 40 publications

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“…Thus, it may regulate cellular differentiation at different sites in different ways. It is noteworthy that when NCI-H292 cells were treated with EGF, only 25% or fewer of the cells became MUC5AC positive in both this study and others (11,59,60). This might reflect heterogeneity in EGF responsiveness and mitotic state of the cells, enabling only a fraction of the cells to respond to Notch signaling, leading to MUC5AC expression.…”

Section: Figurementioning

confidence: 91%

MUC5AC Expression through Bidirectional Communication of Notch and Epidermal Growth Factor Receptor Pathways

Kang

Lee

Park

et al. 2011

The Journal of Immunology

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Hyperproduction of goblet cells and mucin in the airway epithelium is an important feature of airway inflammatory diseases. We investigated the involvement of Notch signaling in MUC5AC expression in NCI-H292 cells, a human lung carcinoma cell line. Epidermal growth factor (EGF) stimulated generation of the Notch intracellular domain (NICD) in a RBP-Jκ–dependent manner. Treatment with γ-secretase inhibitors L-685,458 or DAPT or introduction of small interfering RNA directed against Notch1 reduced EGF-induced MUC5AC expression. The inhibitory effect of L-685,458 on EGF-induced MUC5AC mRNA and protein expression was also observed in primary human bronchial epithelial cells. Blockage of Notch signaling with L-685,458 or Notch siRNA resulted in a decrease in EGF-induced phosphorylation of ERK. These results suggested that ERK activation is necessary for the regulation of EGF receptor (EGFR)–mediated MUC5AC expression by Notch signaling. Conversely, forced expression of NICD induced both EGFR and ERK phosphorylation with MUC5AC expression even in the absence of EGF. Treatment of the NICD-expressing cells with EGF further augmented ERK phosphorylation in an additive manner. The ERK phosphorylation induced by exogenous NICD was inhibited by treatment with an Ab that antagonizes EGFR activity as well as by inhibitors of EGFR and ERK, implying that Notch signaling induces MUC5AC expression by activating the EGFR pathway. Collectively, these results suggest that MUC5AC expression is regulated by a bidirectional circuit between Notch and EGFR signaling pathways.

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Section: Figurementioning

confidence: 91%

MUC5AC Expression through Bidirectional Communication of Notch and Epidermal Growth Factor Receptor Pathways

Kang

Lee

Park

et al. 2011

The Journal of Immunology

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“…Nevertheless, airway diseases with mucous cell hyperplasia, particularly COPD, have elevated levels of these cytokines in the blood as well as in the lungs (39,40). In addition, both IL-1β and TNF-α induce mucous cell hyperplasia in vivo in mouse models (41,42). Both cytokines can also activate NF-κB signaling in airway epithelial cells (43,44), which, as shown above, can lead to the activation of MUC2 expression.…”

Section: Muc2 Expression Regulated By Inflammatory Cytokinesmentioning

confidence: 93%

“…However, another group has shown that TNF-α can also induce MUC5AC expression in NCI-H292 cells through NF-κB. Adenoviral delivery of an IKKB mutant could block MUC5AC's stimulation by TNF-α, both in vitro in human cells as well as in vivo in mice (41).…”

Section: Regulation Of Muc5ac Expression By Nuclear Factor-κbmentioning

confidence: 99%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

192

223

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Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

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“…32) Thus, taken together, it is conceivable that the intracellular signaling coordination by NF-κB activation may be essential for PQ-induced MUC5AC gene expression. Nie et al, demonstrated that MAP kinases signaling pathway is directly implicated in regulation of MUC expression.…”

Section: )mentioning

confidence: 99%

Cytoprotective Effect of Kaempferol on Paraquat-Exposed BEAS-2B Cells <i>via</i> Modulating Expression of <i>MUC5AC</i>

Podder

Song

et al. 2014

Biological & Pharmaceutical Bulletin

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Mucins are highly glycosylated secretary proteins produced by most epithelial cells. Hypersecretion of mucins is one of the prominent symptoms of several airway diseases, including asthma, cystic fibrosis, nasal allergy, rhinitis, and sinusitis. Paraquat (PQ), a common herbicide, has been associated with pulmonary damage and is a potent reactive oxygen species (ROS) producer. However, until now the role of PQ on mucin overproduction has not been studied. The aim of this study is to explore how kaempferol (KM), a widely used dietary flavonoid, affects the protection of human PQ-exposed bronchial epithelium BEAS-2B cells by suppressing Mucin gene expression via nuclear factor-kappa B (NF-κB). We observed that PQ generates intracellular ROS, and also induces lipid peroxidation in BEAS-2B cells. Additionally, we found that PQ effectively induces the expression of the MUC5AC gene; however, co-treatment of PQ with KM drastically reduces its expression. Furthermore, we observed that PQ activates NF-κB, while co-treatment with KM occludes its nuclear translocation, and additionally KM repressed the PQ phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in BEAS-2B cells. Based on our data, we believe that KM can suppress the over-expression of the MUC5AC gene. This would contribute to the protection of PQ cytotoxicity to exposed BEAS-2B cells, and allow further study toward a better understanding of ROSassociated diseases.Key words MUC5AC; kaempferol; reactive oxygen species; human bronchial epithelial BEAS-2B cell; nuclear factor-kappa B Several studies have been carried out demonstrating hypersecretion of mucous from respiratory epithelial cells a major pathological event in chronic airway diseases such as chronic obstructive pulmonary diseases or asthma.1,2) These pathological manifestations are governed by the interaction between underlying genetic factors and xenobiotics, which together are responsible for intercellular reactive oxygen species (ROS) production.3) Findings have shown that ROS such as: hydrogen peroxide, superoxide anion, hydroxyl ion are responsible for the initiation and progression of chronic airway diseases via over-expression of Mucin genes.4-6) ROS is a major etiological factor in the pathogenesis of chronic inflammatory airway diseases as it triggers mucin secretion in epithelia. 7)Twenty different MUC genes have been characterized in human airway epithelia, these are then subdivided into membrane-bound and secreted forms.8-11) MUC5AC is a hallmark gene, and considered the most phenotypical gene in respiratory diseases; it accumulates in respiratory tract can lead to symptoms such as chronic cough and excessive sputum production. Previous studies showed that paraquat (PQ) is a potent ROS inducer in different epithelial cell lines [12][13][14] and is associated with cellular cytoxicity. However, there has been no study into whether PQ can induce MUC gene expression or not, so in this study we investigated the effects of PQ on Bronchial epithelial BEAS...

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Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent Mechanism

Cited by 88 publications

References 40 publications

MUC5AC Expression through Bidirectional Communication of Notch and Epidermal Growth Factor Receptor Pathways

MUC5AC Expression through Bidirectional Communication of Notch and Epidermal Growth Factor Receptor Pathways

Regulation of Airway Mucin Gene Expression

Cytoprotective Effect of Kaempferol on Paraquat-Exposed BEAS-2B Cells <i>via</i> Modulating Expression of <i>MUC5AC</i>

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