Interleukin-13–induced MUC5AC Is Regulated by 15-Lipoxygenase 1 Pathway in Human Bronchial Epithelial Cells

Zhao, Jiang; Maskrey, Ben H.; Balzar, Silvana; Chibana, Kazuyuki; Mustovich, Anthony T.; Hu, Hongsheng; Trudeau, John B.; O'Donnell, Valerie Bridget; Wenzel, Sally E.

doi:10.1164/rccm.200811-1744oc

Cited by 97 publications

(116 citation statements)

References 52 publications

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“…A recent study has shown that a 15-LOX-1 inhibitor abrogates MUC5AC expression induced by long-term IL-13 stimulation of bronchial epithelial cells [22]. However, in the present study, using the same 15-LOX-1 inhibitor reported in the study by ZHAO et al [22], we found that this enzyme is not involved in PMA-induced MUC5AC expression.…”

Section: Discussioncontrasting

confidence: 72%

“…For inhibition studies cells were pretreated with the indicated drugs for 1 h before addition of PMA and inhibitor. Drugs used in the study were tested in a wide range of concentrations (0.1-50 mM) following other studies previously published [15,16,22]. Effects of drugs on MUC5AC expression and cell viability were measured in parallel.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, 15-LOX-1 is involved in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotensin II-dependent hypertension and diabetes [21]. Recently, 15-LOX-1 has been implicated in MUC5AC overexpression in asthma [22].…”

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confidence: 99%

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A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

García-Verdugo¹,

BenMohamed²,

Tattermusch³

et al. 2012

Eur Respir J

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Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism.Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression.Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-a. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation.12R-LOX is involved in MUC5AC expression. This occurs via ERK-and Sp1-signalling pathways.

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Section: Discussioncontrasting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

García-Verdugo¹,

BenMohamed²,

Tattermusch³

et al. 2012

Eur Respir J

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“…6 MUC5B and MUC5AC can be upregulated when human bronchus epithelial cells (HBEC) are cultured with retinoic acid, interleukin (IL)-6, IL-17, and neuroregulin1b1. [7][8][9][10][11] MUC5AC can also be induced in normal HBEC by IL-13, [12][13][14] although inhibited by thyroid hormone and epidermal growth factor. 8 Furthermore, MUC5AC þ GCH induced by IL-13 in normal HBEC depends on activation of IL-13R-JAK-STAT6 and EGFR-MAPK signaling pathways, as well as NF-kB, 15 relevant in allergic asthma as IL-13 is related to the pathogenesis of this disease.…”

mentioning

confidence: 98%

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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“…Although we agree that earlier cell-free experiments suggested arachidonic acid was the preferred substrate for 15LO2, whereas linoleic acid was preferred for 15LO1, in fact, either 15LO1 or -2 can generate 15HETE. Our earlier study strongly suggested 15LO1 was the primary enzyme responsible for 15HETE-PE in the presence of IL-13 in airway epithelial cells (3). No 13S-HODE-PE was detected.…”

Section: S-hete Has Been Considered As a 15-lo2 Metabolite Rather Thanmentioning

confidence: 84%

Reply to Mabalirajan et al.: 15LO1 pathway activation—Are receptors important?

Zhao

Wenzel

2012

Proc. Natl. Acad. Sci. U.S.A.

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Interleukin-13–induced MUC5AC Is Regulated by 15-Lipoxygenase 1 Pathway in Human Bronchial Epithelial Cells

Abstract: Epithelial 15LO1 expression increases with increasing asthma severity. IL-13 induction of 15-HETE-PE enhances MUC5AC expression in human airway epithelial cells. High levels of 15LO1 activity could contribute to the increases of MUC5AC observed in asthma.

Cited by 97 publications

References 52 publications

A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells

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

Reply to Mabalirajan et al.: 15LO1 pathway activation—Are receptors important?

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