Leptin up-regulates MUC5B expression in human airway epithelial cells via mitogen-activated protein kinase pathway

Woo, Hyun‐Jae; Yoo, Woo Jong; Bae, Chang Hoon; Song, Si-Youn; Kim, Yong-Woon; Park, Soyoung; Kim, Yong‐Dae

doi:10.3109/01902140903427033

Cited by 40 publications

(41 citation statements)

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“…Neuregulin 1beta1 [156], leptin [317], cigarette smoke exposure, and reactive oxygen species are also associated with increased expression of MUC5B in vitro [318].…”

Section: Introductionmentioning

confidence: 99%

“…The components of this pathway that have been specifically implicated in MUC5B regulation include p38 MAPK, ERK, NF-κB, MMP-9, ROS, RSK1, CREB, IL-1β, and IL-17A [157,305,309,312,[315][316][317][319][320][321]. This pathway is undoubtedly contributing to the regulation/dysregulation of MUC5B, likely acting through a proximal promoter [322].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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“…Neuregulin 1beta1 [156], leptin [317], cigarette smoke exposure, and reactive oxygen species are also associated with increased expression of MUC5B in vitro [318].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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“…MUC5AC and MUC5B are representative of secreted type mucin genes in human airway [23,24]. These are abnormally upregulated in the inflammatory airway diseases, such as, chronic bronchitis, chronic obstructive pulmonary disease, asthma, and cystic fibrosis [22], and its expression is induced in response to a wide variety of stimuli, such as, nerve activation and inflammatory cytokines, including IL-1β, IL-6, IL-9, IL-13, and tumor necrosis factor-α [25,26]. In addition, several reports have demonstrated that the signaling pathways associated with EGFR or MAPK are responsible for MUC5B expression in airway epithelial cells, for example, Mycoplasma pneumonia was reported to induce MUC5B expression by activating the EGFR signaling pathway [17], and MUC5B expression was found to be up-regulated by PMA (phorbol-12-myristate-13-acetate) through the EGFR/MAPK-independent and -dependent pathways [18].…”

Section: Discussionmentioning

confidence: 99%

High Concentration of Glucose Induces MUC5B Expression via Reactive Oxygen Species in Human Airway Epithelial Cells

Lee¹,

Kim²,

Song³

et al. 2017

Korean J Otorhinolaryngol-Head Neck Surg

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Objectives. Excessive production of mucus results in plugging of the airway tract, which can increase morbidity and mortality in affected patients. In patients with diabetes, inflammatory airway disease appears with more frequent relapse and longer duration of symptoms. However, the effects of high glucose (HG) on the secretion of mucin in inflammatory respiratory diseases are not clear. Therefore, this study was conducted in order to investigate the effect and the brief signaling pathway of HG on MUC5B expression in human airway epithelial cells.Methods. The effect and signaling pathway of HG on MUC5B expression were investigated using reverse transcriptasepolymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassay, and immunoblot analysis with specific inhibitors and small interfering RNA. Results. HG increased MUC5B expression and epidermal growth factor receptor (EGFR) expression, and activated the phosphorylation of EGFR and p38 mitogen-activated protein kinase (MAPK). Pretreatment with EGFR inhibitor sig-nificantly attenuated the HG-induced phosphorylation of p38 MAPK, and pretreatments with p38 inhibitor or EGFR inhibitor significantly attenuated HG-induced MUC5B expression. In addition, knockdown of p38 MAPK by p38 MAPK siRNA significantly blocked HG-induced MUC5B expression.Conclusion. These findings suggest that HG induces MUC5B expression via the sequential activations of the EGFR/p38 MAPK signaling pathway in human airway epithelial cells.

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“…Способность лептина активировать биосинтез лейкотриенов в альвеолярных макрофагах особенно актуально для больных БА, так как активация цистениловых рецепторов приводит к развитию выраженного бронхоспазма [8]. Немаловажную роль в развитии воспаления в дыхательных путях при ожирении играет наличие лептиновых рецепторов на эпителиаль-ных клетках бронхов, которые под действием лептина запускают процесс пролиферации и экспрессии муцина, что приводит к утолщению стенки бронхов и нарушению мукоцилиарного клиренса [12].…”

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