miR-140-3p regulation of TNF-α-induced CD38 expression in human airway smooth muscle cells

Jude, Joseph; Dileepan, Mythili; Subramanian, Subbaya; Solway, Julian; Panettieri, Reynold A.; Walseth, Timothy F.; Kannan, Mathur

doi:10.1152/ajplung.00041.2012

Cited by 92 publications

(80 citation statements)

References 34 publications

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“…Asthmatic ASMCs showed increased histone H3K18 acetylation, and enhanced binding of p300 at the CXCL8 promoter as compared with nonasthmatic ASMCs. On the other hand, ASMCs showed alteration in expression of specific microRNAs in proinflammatory milieu, resulting in aberrant expression of genes modulating ASMC proliferation, hypertrophy, and contractility (15)(16)(17)(18). Furthermore, DNA methylation is the best-studied epigenetic mechanisms in asthma studies.…”

mentioning

confidence: 99%

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Lin

Shang

Mitzner

et al. 2016

Am J Respir Cell Mol Biol

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Airway hyperresponsiveness (AHR) is a hallmark feature in asthma characterized by exaggerated airway contractile response to stimuli due to increased airway sensitivity and chronic airway remodeling. We have previously shown that allergen-induced AHR in mice is associated with aberrant DNA methylation in the lung genome, suggesting that AHR could be epigenetically regulated, and these changes might predispose the animals to asthma. Previous studies demonstrated that overexpression of phosphodiesterase 4D (PDE4D) is associated with increased AHR. However, epigenetic regulation of this gene in asthmatic airway smooth muscle cells (ASMCs) has not been examined. In this study, we aimed to examine the relationship between epigenetic regulation of PDE4D and ASMC phenotypes. We identified CpG site-specific hypomethylation at PDE4D promoter in human asthmatic ASMCs. We next used methylated oligonucleotides to introduce CpG site-specific methylation at PDE4D promoter and examined its effect on ASMCs. We showed that PDE4D methylation decreased cell proliferation and migration of asthmatic ASMCs. We further elucidated that methylated PDE4D decreased PDE4D expression in asthmatic ASMCs, increased cAMP level, and inhibited the aberrant increase in Ca 21 level. Moreover, PDE4D methylation reduced the phosphorylation level of downstream effectors of Ca 21 signaling, including myosin light chain kinase and p38. Taken together, our findings demonstrate that gene-specific epigenetic changes may predispose ASMCs to asthma through alterations in cell phenotypes. Modulation of ASMC phenotypes by methylated PDE4D oligonucleotides can reverse the aberrant ASMC functions to normal phenotypes. This has provided new insight to the development of novel therapeutic options for this debilitative disease.

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mentioning

confidence: 99%

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Lin

Shang

Mitzner

et al. 2016

Am J Respir Cell Mol Biol

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“…It has been known for some time that the proinflammatory phenotype of asthmatics persists in culture, and recent work is uncovering mechanisms for this feature. Molecular mechanisms responsible for elevated cytokineresponsive gene expression in asthmatic hASMCs include histone methylation, histone acetylation, microRNA expression, and altered extracellular matrix profiles (8,21,22,25). Recent understanding of epigenetic mechanisms of gene expression suggest that among these processes, histone posttranslational modifications may be particularly important in establishing a persistent inflammatory phenotype (33).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, reduced histone acetylation and miR-146a expression have been linked to alterations in COX-2 expression in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, respectively (17,20). These regulatory mechanisms have been demonstrated to be altered in asthmatic hASMCs (21,22) but not in the context of COX-2 expression. On this basis we hypothesized that asthmatic hASMCs would express greater amounts of cytokineinduced COX-2 and secrete higher levels of PGE 2 than cells from nonasthmatic subjects because histone acetylation and/or miRNA regulation of COX-2 expression is altered in the asthmatic cells.…”

mentioning

confidence: 99%

Cyclooxygenase-2 and MicroRNA-155 Expression Are Elevated in Asthmatic Airway Smooth Muscle Cells

Comer

Camoretti-Mercado

Kogut³

et al. 2015

Am J Respir Cell Mol Biol

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Cyclooxygenase-2 (COX-2) expression and PGE 2 secretion from human airway smooth muscle cells (hASMCs) may contribute to b 2 -adrenoceptor hyporesponsiveness, a clinical feature observed in some patients with asthma. hASMCs from patients with asthma exhibit elevated expression of cytokine-responsive genes, and in some instances this is attributable to an altered histone code and/or microRNA expression. We hypothesized that COX-2 expression and PGE 2 secretion might be elevated in asthmatic hASMCs in response to proinflammatory signals in part due to altered histone acetylation and/or microRNA expression. hASMCs obtained from nonasthmatic and asthmatic human subjects were treated with cytomix (IL-1b, TNF-a, and IFN-g). A greater elevation of COX-2 mRNA, COX-2 protein, and PGE 2 secretion was observed in the asthmatic cells. We investigated histone H3/H4-acetylation, transcription factor binding, mRNA stability, p38 mitogen-activated protein kinase signaling, and microRNA (miR)-155 expression as potential mechanisms responsible for the differential elevation of COX-2 expression. We found that histone H3/H4-acetylation and transcription factor binding to the COX-2 promoter were similar in both groups, and histone H3/H4-acetylation did not increase after cytomix treatment. Cytomix treatment elevated NF-kB and RNA polymerase II binding to similar levels in both groups. COX-2 mRNA stability was increased in asthmatic cells. MiR-155 expression was higher in cytomix-treated asthmatic cells, and we show it enhances COX-2 expression and PGE 2 secretion in asthmatic and nonasthmatic hASMCs. Thus, miR-155 expression positively correlates with COX-2 expression in the asthmatic hASMCs and may contribute to the elevated expression observed in these cells. These findings may explain, at least in part, b 2 -adrenoceptor hyporesponsiveness in patients with asthma.

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“…Here, cytokines such as TNF-␣ are thought to produce greater increases in CD38 in asthmatic ASM via increased transcriptional regulation involving ERK and p38 MAPK activation [but not NF-B or activated protein (AP)-1, which do regulate CD38 in nonasthmatics] (144). Furthermore, in human asthmatic ASM, TNF-␣ attenuates expression of the microRNA miR-140 -3p that targets the CD38 3=-UTR and influences CD38 stability (142). Interestingly, the same miRNA also modulates TNF-␣ effects on p38 MAPK and NF-B, both of which are relevant to CD38 regulation.…”

Section: L918mentioning

confidence: 98%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

177

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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miR-140-3p regulation of TNF-α-induced CD38 expression in human airway smooth muscle cells

Abstract: MS. miR-140-3p regulation of TNF-␣-induced CD38 expression in human airway smooth muscle cells. Am

Cited by 92 publications

References 34 publications

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Cyclooxygenase-2 and MicroRNA-155 Expression Are Elevated in Asthmatic Airway Smooth Muscle Cells

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

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