Clusterin Induces MUC5AC Expression via Activation of NF-κB in Human Airway Epithelial Cells

Bae, Chang Hoon; Na, Hyung Gyun; Choi, Yoon Seok; Song, Si-Youn; Kim, Yong‐Dae

doi:10.21053/ceo.2017.00493

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…Sol and colleagues have reported that the levels of sputum CLU were significantly lower in asthmatic patients than healthy controls, and moreover, the levels of CLU were associated with asthma severity [ 41 ]. Another study has indicated that CLU was associated with mucus secretion in human airway epithelial cells via activation of NF- κ B [ 42 ]. The present study has indicated a relationship between CLU and CRSwNP, with significantly decreased CLU level in CRSwNP.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Antimicrobial Protein Secretory Leukoprotease Inhibitor and Clusterin in Chronic Rhinosinusitis with Nasal Polyps

Huang

Wang

et al. 2021

Journal of Immunology Research

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Introduction. Antimicrobial peptides and proteins (AMPs) constitute the first line of defense against pathogenic microorganisms in the airway. The association between AMPs and chronic rhinosinusitis with nasal polyps (CRSwNP) requires further investigations. This study is aimed at investigating the expression and regulation of major dysregulated AMPs in the nasal mucosa of CRSwNP. Methods. The expression of AMPs was analyzed in nasal tissue from patients with eosinophilic (E) CRSwNP and nonECRSwNP and healthy subjects using RNA sequencing. The 10 most abundant AMPs expressed differentially in CRSwNP patients were verified by real-time PCR, and of these, the expression and regulation of secretory leukoprotease inhibitor (SLPI) and clusterin (CLU) were investigated further. Results. The 10 most abundant AMPs expressed differentially in CRSwNP compared to healthy control, regardless of subtypes, included BPIFA1, BPIFB1, BPIFB2, CLU, LTF, LYZ, and SLPI, which were downregulated, and S100A8, S100A9, and HIST1H2BC, which were upregulated. ELISA and immunofluorescence confirmed the decreased expression of SLPI and CLU levels in CRSwNP. SLPI is expressed in both nasal epithelial cells and glandular cells, whereas CLU is mainly expressed in glandular cells. AB/PAS staining further demonstrated that both SLPI and CLU were mainly produced by mucous cells in submucosal glands. Furthermore, the numbers of submucosal glands were significantly decreased in nasal polyp tissue of CRSwNP compared to nasal tissue of controls. SLPI was downregulated by TGF-β1 and IL-4 in cultured nasal tissues in vitro, while CLU expression was inhibited by TGF-β1. Glucocorticoid treatment for 2 weeks significantly increased the expression of all downregulated AMPs, but not LYZ. Additionally, budesonide significantly increased the expression of SLPI and CLU in cultured nasal tissues. Conclusion. The expression of major antimicrobial proteins is significantly decreased in nasal tissue of CRSwNP. The expression of SLPI and CLU is correlated with the numbers of submucosal glands and regulated by inflammatory cytokines and glucocorticoids.

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Section: Discussionmentioning

confidence: 99%

Reduced Expression of Antimicrobial Protein Secretory Leukoprotease Inhibitor and Clusterin in Chronic Rhinosinusitis with Nasal Polyps

Huang

Wang

et al. 2021

Journal of Immunology Research

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“…Using comparative microarray profiling, they further indicated that there is a positive correlation between the level of secretory CLU and the expression of many NFκB‐regulated genes. Furthermore, several other groups have also found evidence that CLU increases NFκB activity in various cell types including macrophages, endometrial cancer cells, pancreatic cancer cells, and airway epithelial cells 44‐47 . The factors underlying these conflicting inhibitory and stimulatory effects of CLU on IκB degradation have yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several other groups have also found evidence that CLU increases NFκB activity in various cell types including macrophages, endometrial cancer cells, pancreatic cancer cells, and airway epithelial cells. [44][45][46][47] The factors underlying these conflicting inhibitory and stimulatory effects of CLU on IκB degradation have yet to be elucidated. Interestingly, CLU-mediated inhibition of IκB degradation has been reported in cells of other tissues including neuroblastoma cells, synoviocytes, kidney tubular epithelial cells, cardiocytes, and HeLa cells, none of which is in keeping with the tissues that exhibit increased IκB degradation.…”

Section: F I G U R Ementioning

confidence: 99%

Regulation of adipocyte differentiation by clusterin‐mediated Krüppel‐like factor 5 stabilization

Yoon

Kim

et al. 2020

FASEB j.

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Clusterin (CLU) is a heterodimeric glycoprotein involved in a range of biological processes. We investigated the function of CLU as a novel regulator of adipogenesis. CLU expression increased during 3T3-L1 preadipocyte differentiation. CLU overexpression promoted adipogenic differentiation of preadipocytes and increased the mRNA levels of adipogenic markers including peroxisome proliferator-activated receptor γ (Pparg) and CCAAT enhancer-binding protein α (Cebpa). Conversely, knockdown of CLU attenuated adipogenesis and reduced transcript levels of Pparg and Cebpa. However, the promoter activities of both the Pparg and the Cebpa gene were not affected by alteration of CLU expression on its own. Additionally, the protein level of Krüppel-like factor 5 (KLF5), an upstream transcription factor of Pparg and Cebpa involved in adipogenic differentiation, was upregulated by CLU overexpression, although the mRNA level of Klf5 was not altered by changes in the expression level of CLU. Cycloheximide chase assay showed that the increased level of KLF5 by CLU overexpression was due to decreased degradation of KLF5 protein. Interestingly, CLU increased the stability of KLF5 by decreasing KLF5 ubiquitination. CLU inhibited the interaction between KLF5 and F-box/WD repeat-containing protein 7, which is an E3 ubiquitin ligase that targets KLF5. The adipogenic role of CLU was also addressed in mesenchymal stem cells (MSCs) and Clu −/− mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5-mediated transcriptional activation of both the Cebpa and the Pparg promoter. Taken together, these results suggest that CLU is a novel regulator of adipocyte differentiation by modulating the protein stability of the adipogenic transcription factor KLF5.

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“…The slides were counterstained with hematoxylin and mounted. 14 PAS staining was performed using the PAS staining kit (Merck Millipore, Darmstadt, Germany) according to the manufacturer's protocol. Immunohistochemistry and PAS staining of MUC5AC was analyzed on three different sections in five tissues per group and classified by two independent blinded observers using a semi-quantitative method.…”

Section: Immunohistochemistry (Ihc) and Periodic-acid-schiff (Pas) Stmentioning

confidence: 99%

Benzisothiazolinone upregulates the MUC5AC expression via ERK1/2, p38, and NF-κB pathways in airway epithelial cells

Kwak

Choi

et al. 2019

Toxicology Research

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Mucus plays an important role in protecting the respiratory tract from irritants. However, mucus hypersecretion is a major indicator of airway diseases. 1,2-Benzisothiazolin-3-one (BIT), as a microbicide, induces asthmatic inflammation. Therefore, we focused on the effects of BIT-related mucin secretion in airway epithelial cells. Our in vivo study showed increased mucus and MUC5AC expressions in the bronchioles of mice that inhaled BIT. For investigating the signaling pathways, we performed experiments in human airway epithelial cells. BIT induced the MUC5AC expression and significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The specific inhibitors of ERK1/2, p38, and NF-κB blocked the BIT-induced MUC5AC expression. Therefore, these results suggest that BIT induces the MUC5AC expression via the ERK1/2, p38, and NF-κB pathways in human airway epithelial cells, which may be involved in mucus hypersecretion associated with airway inflammatory diseases.

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Clusterin Induces MUC5AC Expression via Activation of NF-κB in Human Airway Epithelial Cells

Cited by 13 publications

References 31 publications

Reduced Expression of Antimicrobial Protein Secretory Leukoprotease Inhibitor and Clusterin in Chronic Rhinosinusitis with Nasal Polyps

Reduced Expression of Antimicrobial Protein Secretory Leukoprotease Inhibitor and Clusterin in Chronic Rhinosinusitis with Nasal Polyps

Regulation of adipocyte differentiation by clusterin‐mediated Krüppel‐like factor 5 stabilization

Benzisothiazolinone upregulates the MUC5AC expression via ERK1/2, p38, and NF-κB pathways in airway epithelial cells

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