Transcriptional Regulation of Inflammatory Genes Associated with Severe Asthma

Clifford, Rachel L.; Coward, William R.; Knox, Alan J.; John, Alison E.

doi:10.2174/138161211795429000

Cited by 8 publications

(5 citation statements)

References 200 publications

(249 reference statements)

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“…VEGF levels relate to asthma severity and airflow obstruction (5). The grossly thickened airway smooth muscle is an important cellular source of chemokines and growth factors in asthma (6, 7) and recent studies have shown VEGF hypersecretion from asthmatic human airway smooth muscle (HASM) cells (8). However information regarding the molecular mechanism of VEGF hypersecretion is scant.…”

Section: Introductionmentioning

confidence: 99%

Abnormal Histone Methylation Is Responsible for Increased Vascular Endothelial Growth Factor 165a Secretion from Airway Smooth Muscle Cells in Asthma

Clifford

John

Brightling

et al. 2012

The Journal of Immunology

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Vascular endothelial growth factor (VEGF), a key angiogenic molecule, is aberrantly expressed in several diseases including asthma where it contributes to bronchial vascular remodeling and chronic inflammation. Asthmatic human airway smooth muscle cells hypersecrete VEGF, but the mechanism is unclear. In this study, we defined the mechanism in human airway smooth muscle cells from nonasthmatic and asthmatic patients. We found that asthmatic cells lacked a repression complex at the VEGF promoter, which was present in nonasthmatic cells. Recruitment of G9A, trimethylation of histone H3 at lysine 9 (H3K9me3), and a resultant decrease in RNA polymerase II at the VEGF promoter was critical to repression of VEGF secretion in nonasthmatic cells. At the asthmatic promoter, H3K9me3 was absent because of failed recruitment of G9a; RNA polymerase II binding, in association with TATA-binding protein-associated factor 1, was increased; H3K4me3 was present; and Sp1 binding was exaggerated and sustained. In contrast, DNA methylation and histone acetylation were similar in asthmatic and nonasthmatic cells. This is the first study, to our knowledge, to show that airway cells in asthma have altered epigenetic regulation of remodeling gene(s). Histone methylation at genes such as VEGF may be an important new therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Abnormal Histone Methylation Is Responsible for Increased Vascular Endothelial Growth Factor 165a Secretion from Airway Smooth Muscle Cells in Asthma

Clifford

John

Brightling

et al. 2012

The Journal of Immunology

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“…These phenomena are not nearly as well defined in smooth muscle cells as they are in cardiac muscle cancer cells and the immune system. [1–3]…”

Section: Introductionmentioning

confidence: 99%

“…These phenomena are not nearly as well defined in smooth muscle cells as they are in cardiac muscle cancer cells and the immune system. [1][2][3] The goal of this review is to summarize emerging knowledge of the microRNA (miRNA) class of small, noncoding RNAs in vascular smooth muscle cell phenotypes in normal tissue and in pulmonary diseases. We will focus on miRNAs with validated targets that are relevant to smooth muscle contractility and vascular development.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs‐Control of Essential Genes: Implications for Pulmonary Vascular Disease

et al. 2011

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During normal lung development and in lung diseases structural cells in the lungs adapt to permit changes in lung function. Fibroblasts, myofibroblasts, smooth muscle, epithelial cells, and various progenitor cells can all undergo phenotypic modulation. In the pulmonary vasculature occlusive vascular lesions that occur in severe pulmonary arterial hypertension are multifocal, polyclonal lesions containing cells presumed to have undergone phenotypic transition resulting in altered proliferation, cell lifespan or contractility. Dynamic changes in gene expression and protein composition that underlie processes responsible for such cellular plasticity are not fully defined. Advances in molecular biology have shown that multiple classes of ribonucleic acid (RNA) collaborate to establish the set of proteins expressed in a cell. Both coding Messenger Ribonucleic acid (mRNA) and small noncoding RNAs (miRNA) act via multiple parallel signaling pathways to regulate transcription, mRNA processing, mRNA stability, translation and possibly protein lifespan. Rapid progress has been made in describing dynamic features of miRNA expression and miRNA function in some vascular tissues. However posttranscriptional gene silencing by microRNA-mediated mRNA degradation and translational blockade is not as well defined in the pulmonary vasculature. Recent progress in defining miRNAs that modulate vascular cell phenotypes is reviewed to illustrate both functional and therapeutic significance of small noncoding RNAs in pulmonary arterial hypertension.

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“…Smooth muscle cells are considered to play a central role in orchestration of the inflammatory response within the bronchial wall (6). MCP-1 secretion from human ASM cells was first described in 1998 (28), and since then its regulation by various stimuli has been investigated.…”

mentioning

confidence: 99%

Ciclesonide inhibits TNFα- and IL-1β-induced monocyte chemotactic protein-1 (MCP-1/CCL2) secretion from human airway smooth muscle cells

Patel

Clifford

Deacon

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Monocyte chemotactic protein-1 (MCP-1) is a member of the CC family of cytokines. It has monocyte and lymphocyte chemotactic activity and stimulates histamine release from basophils. MCP-1 is implicated in the pathogenesis of inflammatory diseases, including asthma. The airway smooth muscle (ASM) layer is thickened in asthma, and the growth factors and cytokines secreted by ASM cells play a role in the inflammatory response of the bronchial wall. Glucocorticoids and β2-agonists are first-line drug treatments for asthma. Little is known about the effect of asthma treatments on MCP-1 production from human ASM cells. Here, we determined the effect of ciclesonide (a glucocorticoid) and formoterol (a β2-agonist) on MCP-1 production from human ASM cells. TNFα and IL-1β induced MCP-1 secretion from human ASM cells. Formoterol had no effect on MCP-1 expression, while ciclesonide significantly inhibited IL-1β- and TNFα-induced MCP-1. Furthermore, ciclesonide inhibited IL-1β- and TNFα-induced MCP-1 mRNA and IL-1β- and TNFα-induced MCP-1 promoter and enhancer luciferase reporters. Western blots showed that ciclesonide had no effect on IκB degradation. Finally, ciclesonide inhibited an NF-κB luciferase reporter. Our data show that ciclesonide inhibits IL-1β- and TNFα-induced MCP-1 production from human ASM cells via a transcriptional mechanism involving inhibition of NF-κB binding.

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Transcriptional Regulation of Inflammatory Genes Associated with Severe Asthma

Cited by 8 publications

References 200 publications

Abnormal Histone Methylation Is Responsible for Increased Vascular Endothelial Growth Factor 165a Secretion from Airway Smooth Muscle Cells in Asthma

Abnormal Histone Methylation Is Responsible for Increased Vascular Endothelial Growth Factor 165a Secretion from Airway Smooth Muscle Cells in Asthma

MicroRNAs‐Control of Essential Genes: Implications for Pulmonary Vascular Disease

Ciclesonide inhibits TNFα- and IL-1β-induced monocyte chemotactic protein-1 (MCP-1/CCL2) secretion from human airway smooth muscle cells

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