IL-8 Regulates Mucin Gene Expression at the Posttranscriptional Level in Lung Epithelial Cells

Bautista, Manuel; Chen, Yajun; Ivanova, Vessela S.; Rahimi, Michael; Watson, Alan M.; Rose, Mary C.

doi:10.4049/jimmunol.0803022

Cited by 93 publications

(65 citation statements)

References 56 publications

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“…Sputum CXCL8/IL-8 has long been recognised to play a prominent role in COPD [30,31]. It induces airway inflammation by predominantly recruiting neutrophils and upregulating airway mucin genes, resulting in mucus production [32]. Elevated sputum CXCL8/IL-8 levels are associated with elevated COPD severity [30,33,34].…”

Section: Network Analysis Reveals Potential Microbiota Interactionsmentioning

confidence: 99%

Lung microbiome dynamics in COPD exacerbations

et al. 2016

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Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics. @ERSpublications Lung microbiome changes are associated with COPD exacerbation events and implicated in host inflammatory responses

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Section: Network Analysis Reveals Potential Microbiota Interactionsmentioning

confidence: 99%

Lung microbiome dynamics in COPD exacerbations

et al. 2016

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“…The most abundant mucins expressed are MUC1, MUC2, and MUC5AC; each is induced by a variety of grampositive and gram-negative pathogens as well as viruses (46)(47)(48)(49)(50)(51). Induction of mucin gene expression has been observed with TNF (52) and CXCL8 (53). Direct stimulation of TLR2 (54) and TLR3 (55) induces mucin expression as well as activating MAPK (56) and inducing epidermal growth factor receptor (EGFR) signaling (55,57).…”

Section: Tlr Regulation Of Mucin Productionmentioning

confidence: 99%

Innate Immunity in the Respiratory Epithelium

Parker

Prince

2011

Am J Respir Cell Mol Biol

391

404

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The airway epithelium represents the first point of contact for inhaled foreign organisms. The protective arsenal of the airway epithelium is provided in the form of physical barriers and a vast array of receptors and antimicrobial compounds that constitute the innate immune system. Many of the known innate immune receptors, including the Toll-like receptors and nucleotide oligomerization domain-like receptors, are expressed by the airway epithelium, which leads to the production of proinflammatory cytokines and chemokines that affect microorganisms directly and recruit immune cells, such as neutrophils and T cells, to the site of infection. The airway epithelium also produces a number of resident antimicrobial proteins, such as lysozyme, lactoferrin, and mucins, as well as a swathe of cationic proteins. Dysregulation of the airway epithelial innate immune system is associated with a number of medical conditions that can result in compromised immunity and chronic inflammation of the lung. This review focuses on the innate immune capabilities of the airway epithelium and its role in protecting the lung from infection as well as the outcomes when its function is compromised.

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“…Not surprisingly, many immune stimulants were found to increase MUC5B expression including visfatin (proinflammatory adipocytokine) [309], lipopolysaccharide [310], IL-13 [311], adenosine monophosphate-activated protein kinase [312], monocyte chemotactic protein 1 [313], IL-8 [314], prostaglandin [315], and staphylococcus enterotoxin A [316].…”

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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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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IL-8 Regulates Mucin Gene Expression at the Posttranscriptional Level in Lung Epithelial Cells

Cited by 93 publications

References 56 publications

Lung microbiome dynamics in COPD exacerbations

Lung microbiome dynamics in COPD exacerbations

Innate Immunity in the Respiratory Epithelium

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

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