Regulation of Airway <i>MUC5AC</i> Expression by IL-1β and IL-17A; the NF-κB Paradigm

Fujisawa, Tomoyuki; Velichko, Sharlene; Thai, Phung N.; Hung, Li-Yin; Huang, Fei; Wu, Reen

doi:10.4049/jimmunol.0900614

Cited by 220 publications

(215 citation statements)

References 49 publications

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“…Partial inhibition of MUC5AC was induced by supernatant from LPS-treated MDM in contrast to the consistent increase of MUC5AC generated by a mix of pro-inflammatory cytokines, as well as by TNF-a and IL-1b alone, at levels found in MDM supernatant. However, our findings are in agreement with reports showing that IL-1b [47][48][49] and TNF-a 47 induce MUC5AC mRNA expression in HBEC. Additionally, significant inhibition of MUC5AC was observed in HBEC treated with supernatant from control MDM, whereas lack of consistent MUC5AC changes were observed in HBEC challenged with cytokines mimicking supernatant from control MDM.…”

Section: Discussionsupporting

confidence: 93%

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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Airway goblet cell hyperplasia (GCH)-detectable by mucin staining-and abnormal macrophage infiltrate are pathological features present in many chronic respiratory disorders. However, it is unknown if both factors are associated. Using in-vivo and in-vitro models, we investigated whether macrophages are related with GCH and changes in mucin immunophenotypes. Lung sections from Sprague-Dawley rats treated for 48 h with one intra-tracheal dose of PBS or LPS (n ¼ 4-6 per group) were immunophenotyped for rat-goblet cells, immune, and proliferation markers. Human monocytederived macrophages (MDM) were pre-treated with or without LPS, immunophenotyped, and their supernatant, as well as cytokines at levels equivalent to supernatant were used to challenge primary culture of normal human bronchus epithelial cells (HBEC) in air-liquid interface, followed by MUC5B and MUC5AC mucin immunostaining. An association between increased bronchiolar goblet cells and terminal-bronchiolar proliferative epithelial cells confirmed the presence of GCH in our LPS rat model, which was related with augmented bronchiolar CD68 macrophage infiltration. The in-vitro experiments have shown that MUC5AC phenotype was inhibited when HBEC were challenged with supernatant from MDM pre-treated with or without LPS. In contrast, TNF-a and interleukin-1b at levels equivalent to supernatant from LPS-treated MDM increased MUC5AC. MUC5B was induced by LPS, supernatant from LPS-treated MDM, a mix of cytokines including TNF-a and TNF-a alone at levels present in supernatant from LPS-treated MDM. We demonstrated that macrophages are related with bronchiolar GCH, and that they induced MUC5B and inhibited MUC5AC in HBEC, suggesting a role for them in the pathogenesis of airway MUC5B-related GCH. KEYWORDS: airways; cytokines; LPS; lung inflammation; TNF-alphaMucus is a gel that covers the airway epithelium and is constituted by different glycoproteins called mucins, which are secreted by goblet cells from submucosal glands and the airway epithelium. 1 Mucus dissolves noxious gases and entraps foreign particles and pathogens, facilitating their clearance by mucociliary transport as a mechanism of innate defense. 2 However, in chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), there is a pathological goblet cell hyperplasia (GCH) and mucus hypersecretion that can generate airway occlusion, associated with morbidity and death. 1 The main gel-forming mucins found in human airways are MUC5B and MUC5AC. 1 In healthy individuals, low levels of MUC5B and MUC5AC can be detected in mucus; although MUC5B is mainly present in the submucosal glands and MUC5AC is predominantly distributed in the airway epithelium. 3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GC...

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Section: Discussionsupporting

confidence: 93%

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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“…We now provide strong evidence that IL13 can act as a secretagogue for MUC5AC in human airway epithelial cells. The magnitude and timing (within an hour) of this effect was similar to the known secretagogue ATP-g-S. Other cytokines such as IL1B (interleukin 1, b) increase MUC5AC production 48 and secretion. 49 However, the effect was delayed for hours or days, suggesting that a secondary pathway was utilized for mucus production.…”

Section: Discussionmentioning

confidence: 69%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

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“…Besides, periostin is increasingly used as a clinical biomarker for eosinophilic asthma (28). IL-4, IL-5, IL-13, IL-17, IL-33, and TNF-a have all been shown to promote MUC5AC expression and goblet cell hyperplasia, and MUC5AC gene expression hinges on the transcriptional activity of NF-kB (29). IL-4 and IL-13 induce B cells to undergo isotype class switching to IgE production (30), and IgE cross-linking with FcεRI on mast cells leads to mast cell degranulation and bronchoconstriction (31).…”

Section: Discussionmentioning

confidence: 99%

“…IL-17 and G-CSF can contribute to the neutrophilic lung inflammation (33,34), and IL-17 has also been linked to the development of steroid-resistant asthma. The observed anti-inflammatory effects of g-tocotrienol in HDM-induced experimental asthma are likely due to its inhibition on NF-kB activation, as many of those proinflammatory genes encoding for TNF-a, IL-17, MUC5AC, VCAM-1, RANTES, and E-selectin contain the kB site for NF-kB binding within their promoter regions and/or act through NF-kB signaling pathway (4,29).…”

Section: Discussionmentioning

confidence: 99%

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

Peh

Chang

et al. 2015

The Journal of Immunology

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Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.

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Regulation of Airway MUC5AC Expression by IL-1β and IL-17A; the NF-κB Paradigm

Cited by 220 publications

References 49 publications

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

IL13 activates autophagy to regulate secretion in airway epithelial cells

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

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