Key Role for Store-Operated Ca2+ Channels in Activating Gene Expression in Human Airway Bronchial Epithelial Cells

Samanta, Krishna; Bakowski, Daniel; Parekh, Anant B.

doi:10.1371/journal.pone.0105586

Cited by 25 publications

(39 citation statements)

References 46 publications

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“…The rates of Ca 2+ influx following Ca 2+ add-back reflect store-operated channel activity and are summarized in Figure 3E. These findings are consistent with recent reports indicating presence of CRAC channels in the bronchial cell lines 16HBE and CFBE410 − (21, 34). …”

Section: Resultssupporting

confidence: 89%

“…1). These findings confirm and broaden observations from past studies that have described STIM1 and Orai1 mediated SOCE in various airway epithelial cell-lines and corroborate the emerging viewpoint that CRAC channels are a well conserved mechanism for Ca 2+ influx in the lower airways (21, 34, 53). Our data however do not rule out a role for other CRAC channel isoforms.…”

Section: Discussionsupporting

confidence: 90%

“…Previous evidence indicates that the CRAC channel proteins Orai1 and STIM1 are expressed in the lung (21, 34), raising the possibility that these proteins may contribute to Ca 2+ signaling in AECs. We therefore sought to investigate the contribution of STIM1 and Orai1 to PAR2 evoked Ca 2+ signals.…”

Section: Resultsmentioning

confidence: 99%

“…As a multifunctional second messenger, Ca 2+ activates distinct genetic programs and enzymatic cascades to regulate many processes in the immune system including lymphocyte activation, mast-cell degranulation and neutrophil mediated bacterial killing (15–18). There is growing interest in the role of cellular Ca 2+ as a key second messenger regulating effector responses in the airway (19–21). Yet the functional architecture of the Ca 2+ signaling network: the molecular entities and their organization, and how this machinery regulates Ca 2+ signaling and PAR2 evoked effector responses remains poorly understood in airway epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells

Jairaman

Yamashita

Schleimer

et al. 2015

The Journal of Immunology

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The G-protein coupled protease-activated receptor 2 (PAR2) plays an important role in the pathogenesis of various inflammatory and auto-immune disorders. In airway epithelial cells (AECs), stimulation of PAR2 by allergens and proteases triggers the release of a host of inflammatory mediators to regulate bronchomotor tone and immune cell recruitment. Activation of PAR2 turns on several cell signaling pathways of which the mobilization of cytosolic Ca2+ is likely a critical but poorly understood event. Here, we show that Ca2+ release-activated Ca2+ (CRAC) channels encoded by STIM1 and Orai1 are a major route of Ca2+ entry in primary human AECs and drive the Ca2+ elevations seen in response to PAR2 activation. Activation of CRAC channels induces the production of several key inflammatory mediators from AECs including TSLP, IL-6 and PGE2, in part through stimulation of gene expression via NFAT (nuclear factor of activated T-cells). Furthermore, PAR2 stimulation induces the production of many key inflammatory mediators including PGE2, IL-6, IL-8 and GM-CSF in a CRAC-channel dependent manner. These findings indicate that CRAC channels are the primary mechanism for Ca2+ influx in AECs and a vital checkpoint for the induction of PAR2-induced proinflammatory cytokines.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells

Jairaman

Yamashita

Schleimer

et al. 2015

The Journal of Immunology

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“…We and others have shown that CRAC channels are a major mechanism for eliciting Ca 2+ signals in AECs and are activated in response to PAR2 stimulation1516. The ensuing Ca 2+ elevation regulates the production of key inflammatory cytokines including IL-6, IL-8, and TSLP15.…”

mentioning

confidence: 98%

Allergens stimulate store-operated calcium entry and cytokine production in airway epithelial cells

Jairaman

Maguire

Schleimer

et al. 2016

Sci Rep

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Aberrant immune responses to environmental allergens including insect allergens from house dust mites and cockroaches contribute to allergic inflammatory diseases such as asthma in susceptible individuals. Airway epithelial cells (AECs) play a critical role in this process by sensing the proteolytic activity of allergens via protease-activated receptors (PAR2) to initiate inflammatory and immune responses in the airway. Elevation of cytosolic Ca2+ is an important signaling event in this process, yet the fundamental mechanism by which allergens induce Ca2+ elevations in AECs remains poorly understood. Here we find that extracts from dust mite and cockroach induce sustained Ca2+ elevations in AECs through the activation of Ca2+ release-activated Ca2+ (CRAC) channels encoded by Orai1 and STIM1. CRAC channel activation occurs, at least in part, through allergen mediated stimulation of PAR2 receptors. The ensuing Ca2+ entry then activates NFAT/calcineurin signaling to induce transcriptional production of the proinflammatory cytokines IL-6 and IL-8. These findings highlight a key role for CRAC channels as regulators of allergen induced inflammatory responses in the airway.

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Flavonoids as Cytokine Immunomodulators to Reduce Airway Inflammation via Inhibition of the NF‐κB Signalling Pathway: A Systematic Overview

Gandhi¹,

Dhanabalan²,

Vasconcelos³

et al. 2020

Encyclopedia of Life Sciences

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Asthma is a chronic inflammatory respiratory disease with increasing prevalence which has been linked to the interaction of genetic and environmental factors. Specific types of infections and environmental exposure, alongside a predisposed set of genes, can lead to a systemic propensity for allergic T‐helper (Th) type 2 cells to induce cytokine responses, resulting in allergic airway inflammation. The key event in the pathogenesis of asthma is infiltration of inflammatory cells into the airways and lungs, resulting in mucus hypersecretion and intermittent obstructive events. Cytokines play a vital role in the pathogenesis of immune responses and also have a complex mode of action in inflammatory processes. Peer‐reviewed articles investigating flavonoids with therapeutic evidence for the management of asthma were acquired from Pubmed, Embase, Scopus and Web of Science. We provide an extensive overview of the modulation of cytokines by flavonoids to assess how these natural products trigger immune responses, modulate immunity and lower airway inflammation. Seventeen flavonoids were reported as cytokine modulators of nuclear transcription factor kappa B (NF‐κB) signalling in the identified articles. These flavonoids predominantly modulated the release of the production and expressions of the pro‐ and anti‐inflammatory cytokines TNF‐α, IL‐1β, IL‐8, Th17 (IL‐17), Th1 (IFN‐γ, IL‐2 and IL‐12) and Th2 (IL‐4, IL‐5, IL‐6 and IL‐13), inhibited eosinophil infiltration and decreased the activity and expression of NF‐κB. Key Concepts Bronchial asthma is a chronic inflammatory airway syndrome which endangers human health. Corticosteroids and β2‐agonists are effective drugs for asthma; however, their prolonged use is associated with side effects such as drug tolerance, osteoporosis and immune suppression. Asthma increases the number of inflammatory cells such as eosinophils and lymphocytes in peripheral blood, bronchoalveolar lavage fluid (BALF) and lung tissue and immunoglobulin E (IgE). Flavonoids are plant‐derived active compounds reputed to have therapeutic potential. The use of flavonoids in experimentally induced asthma models is associated with lower levels of Th2 cytokines such as IL‐4, IL‐5, IL‐6 and IL‐13 and modulation of pro‐inflammatory cytokines such as TNF‐α, IL‐1β and IL‐8. Flavonoids generally inhibit pulmonary nuclear transcription factor kappa‐B (NF‐κB) or mitogen‐activated protein kinase (MAPK) signalling pathways and reduce airway inflammation in experimental models. Flavonoids reduce airway hyperresponsiveness, mucus cell hyperplasia and fixed airway flow obstruction. Flavonoids demonstrated significant in vitro and in vivo properties in animal models on homeostasis within the immune system and on the inflammatory response.

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Key Role for Store-Operated Ca2+ Channels in Activating Gene Expression in Human Airway Bronchial Epithelial Cells

Cited by 25 publications

References 46 publications

Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells

Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells

Allergens stimulate store-operated calcium entry and cytokine production in airway epithelial cells

Flavonoids as Cytokine Immunomodulators to Reduce Airway Inflammation via Inhibition of the NF‐κB Signalling Pathway: A Systematic Overview

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