Association Between IL-1 β /TNF- α –Induced Glucocorticoid-Sensitive Changes in Multiple Gene Expression and Altered Responsiveness in Airway Smooth Muscle

2001 ◽  
Vol 25 (6) ◽  
pp. 761-771 ◽  
Author(s):  
Hakon Hakonarson ◽  
Eva Halapi ◽  
Russell Whelan ◽  
Jeffrey Gulcher ◽  
Kari Stefansson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Multiple Gene ◽  
Tnf Α

scholarly journals Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Priyanka Banerjee ◽  
Premanand Balraj ◽  
Nilesh Sudhakar Ambhore ◽  
Sarah A. Wicher ◽  
Rodney D. Britt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Airway Smooth Muscle Cell ◽  
Gene Interactions ◽  
Regulatory Relationship ◽  
Multiple Gene ◽  
Asthma Exacerbations ◽  
Asthmatic Group

AbstractAirway smooth muscle (ASM) is known for its role in asthma exacerbations characterized by acute bronchoconstriction and remodeling. The molecular mechanisms underlying multiple gene interactions regulating gene expression in asthma remain elusive. Herein, we explored the regulatory relationship between ASM genes to uncover the putative mechanism underlying asthma in humans. To this end, the gene expression from human ASM was measured with RNA-Seq in non-asthmatic and asthmatic groups. The gene network for the asthmatic and non-asthmatic group was constructed by prioritizing differentially expressed genes (DEGs) (121) and transcription factors (TFs) (116). Furthermore, we identified differentially connected or co-expressed genes in each group. The asthmatic group showed a loss of gene connectivity due to the rewiring of major regulators. Notably, TFs such as ZNF792, SMAD1, and SMAD7 were differentially correlated in the asthmatic ASM. Additionally, the DEGs, TFs, and differentially connected genes over-represented in the pathways involved with herpes simplex virus infection, Hippo and TGF-β signaling, adherens junctions, gap junctions, and ferroptosis. The rewiring of major regulators unveiled in this study likely modulates the expression of gene-targets as an adaptive response to asthma. These multiple gene interactions pointed out novel targets and pathways for asthma exacerbations.

scholarly journals Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells: role of dual specificity phosphatase 1

2008 ◽  
Vol 295 (1) ◽  
pp. L186-L193 ◽  
Author(s):  
Bit Na Kang ◽  
Joseph A. Jude ◽  
Reynold A. Panettieri ◽  
Timothy F. Walseth ◽  
Mathur S. Kannan
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Posttranscriptional Regulation ◽  
Airway Smooth Muscle Cells ◽  
Small Interfering Rnas ◽  
Human Airway Smooth Muscle ◽  
Transcript Stability ◽  
Human Airway ◽  
Cd38 Expression ◽  
Tnf Α

The enzymatic activity of CD38, ADP-ribosyl cyclase, synthesizes the calcium mobilizing molecule cyclic ADP-ribose from β-NAD. In human airway smooth muscle (HASM) cells, CD38 expression is augmented by the inflammatory cytokine, TNF-α, causing increased intracellular calcium response to agonists. The transcriptional and posttranscriptional regulation of CD38 expression involves signaling through MAPKs and requires activation of NF-κB and activator protein-1 (AP-1). The cytokine-augmented CD38 expression is decreased by anti-inflammatory glucocorticoids due to inhibition of NF-κB activation and other mechanisms. In this study, we investigated glucocorticoid regulation of CD38 expression in HASM cells through the MKP-1. In HASM cells, dexamethasone and TNF-α induced MKP-1 expression (both mRNA and protein) rapidly. Dexamethasone decreased TNF-α-induced phosphorylation of the major MAPKs, i.e., ERK, p38, and JNK, and decreased the activation of NF-κB and AP-1. Dexamethasone also decreased CD38 expression induced by TNF-α, and part of this effect was attributable to decreased transcript stability. In cells transfected with MKP-1-specific small interfering RNAs (siRNAs), there was significant attenuation of MKP-1 expression and partial, but nonsignificant, reversal of dexamethasone inhibition of CD38 expression. These results indicate that regulation of CD38 expression in HASM cells by glucocorticoids involves decreased signaling through MAPKs and activation of transcription factors. The glucocorticoid effects on decreased CD38 expression and function result from regulation through transcription and transcript stability.

Raf-1 kinase mediates adenylyl cyclase sensitization by TNF-α in human airway smooth muscle cells

2007 ◽  
Vol 292 (6) ◽  
pp. L1414-L1421 ◽  
Author(s):  
Yoko Osawa ◽  
Peter D. Yim ◽  
Dingbang Xu ◽  
Reynold A. Panettieri ◽  
Charles W. Emala
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Adenylyl Cyclase ◽  
Airway Smooth Muscle ◽  
Egf Receptor ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tnf Α

Tumor necrosis factor (TNF)-α is a potent inflammatory cytokine implicated in the exacerbation of asthma. Chronic exposure to TNF-α has been reported to induce G protein-coupled receptor desensitization, but adenylyl cyclase sensitization, in airway smooth muscle cells by an unknown mechanism. Cyclic AMP, which is synthesized by adenylyl cyclases in response to G protein-coupled receptor signals, is an important second messenger involved in the regulation of the airway muscle proliferation, migration, and tone. In other cell types, TNF-α receptors transactivate the EGF receptor, which activates raf-1 kinase. Further studies in transfected cells show that raf-1 kinase can phosphorylate and activate some isoforms of adenylyl cyclase. Cultured human airway smooth muscle cells were treated with TNF-α in the presence or absence of inhibitors of prostaglandin signaling, protein kinases, or Gi proteins. TNF-α caused a significant dose- (1–10 ng/ml) and time-dependent (24 and 48 h) increase in forskolin-stimulated adenylyl cyclase activity, which was abrogated by pretreatment with GW5074 (a raf-1 kinase inhibitor), was partially inhibited by an EGF receptor inhibitor, but was unaffected by pertussis toxin. TNF-α also increased phosphorylation of Ser338 on raf-1 kinase, indicative of activation. IL-1β and EGF sensitization of adenylyl cyclase activity was also sensitive to raf-1 kinase inhibition by GW5074. Taken together, these studies link two signaling pathways not previously characterized in human airway smooth muscle cells: TNF-α transactivation of the EGF receptor, with subsequent raf-1 kinase-mediated activation of adenylyl cyclase.

691: Vitamin D reduces TNF-α induced MMP-9 activity in human fetal airway smooth muscle cells

2014 ◽  
Vol 210 (1) ◽  
pp. S340
Author(s):  
Arij Faksh ◽  
Rodney Britt ◽  
Elizabeth Vogel ◽  
Elizabeth Baldwin ◽  
Mari Charisse Trinidad ◽  
...  
Keyword(s):  
Vitamin D ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Tnf Α

Selected Contribution: Synergism between TNF-α and IL-1β in airway smooth muscle cells: implications for β-adrenergic responsiveness

2001 ◽  
Vol 91 (3) ◽  
pp. 1467-1474 ◽  
Author(s):  
Paul E. Moore ◽  
Thomas Lahiri ◽  
Johanne D. Laporte ◽  
Trudi Church ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Nuclear Factor Κb ◽  
Airway Smooth Muscle Cells ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Combined Administration ◽  
Cox 2

In human cultured airway smooth muscle cells, interleukin (IL)-1β increases cyclooxygenase (COX)-2 expression and PGE2 release, ultimately resulting in decreased β-adrenergic responsiveness. In this study, we aimed to determine whether tumor necrosis factor-α (TNF-α) synergizes with IL-1β in the induction of these events. TNF-α alone, at concentrations up to 10 ng/ml, had no effect on COX-2 protein expression; at concentrations as low as 0.1 ng/ml, it significantly enhanced the ability of IL-1β (0.2 ng/ml) to induce COX-2 and to increase PGE2 release. IL-1β and TNF-α in combination also significantly enhanced COX-2 promoter activity, indicating that synergism between the cytokines is mediated at the level of gene transcription. Although IL-1β and TNF-α each increased nuclear factor-κB activation and induced extracellular regulated kinase and p38 phosphorylation, combined administration of the cytokines did not enhance either nuclear factor-κB or mitogen-activated protein kinase activation. Combined administration of IL-1β (0.2 ng/ml) and TNF-α (0.1 or 1.0 ng/ml) reduced the ability of isoproterenol to decrease human airway smooth muscle cell stiffness, as measured by magnetic twisting cytometry, even though individually these cytokines, at these concentrations, had no effect on isoproterenol responses. Treatment with the selective COX-2 inhibitor NS-398 abolished the synergistic effects of TNF-α and IL-1β on β-adrenergic responsiveness. Our results indicate that low concentrations of IL-1β and TNF-α synergize to promote β-adrenergic hyporesponsiveness and that effects on COX-2 expression and PGE2 are responsible for these events. The data suggest that the simultaneous release in the airway, of even very small amounts of cytokines, can have important functional consequences.

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