Prostaglandin E<sub>2</sub> Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Activity and Airway Surface Liquid Volume Requires Gap Junctional Communication

Scheckenbach, Klaus Ernst Ludwig; Losa, Davide; Dudez, Tecla; Bacchetta, Marc; O’Grady, Scott M.; Crespin, Sophie; Chanson, Marc

doi:10.1165/rcmb.2009-0361oc

Cited by 25 publications

(30 citation statements)

References 40 publications

(54 reference statements)

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“…An interaction between the CFTR ABC transporter and connexins has recently been suggested in airway epithelial cells [40]. To determine whether both the MDR1 ABC transporter and connexin hemichannels were involved in air-stimulated ATP release, uptake of the connexin permeable dye LY and exclusion of the radiolabeled MDR1 substrate [ 3 H]-digoxin were measured following air exposure (Figures 4 and 5, respectively).…”

Section: Resultsmentioning

confidence: 99%

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

et al. 2013

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Cutaneous ATP release plays an important role in both epidermal stratification and chronic pain, but little is known about ATP release mechanisms in keratinocytes that comprise the epidermis. In this study, we analyzed ATP release from cultured human neonatal keratinocytes briefly exposed to air, a process previously demonstrated to trigger ATP release from these cells. We show that exposing keratinocytes to air by removing media for 15 seconds causes a robust, long-lasting ATP release. This air-stimulated ATP release was increased in calcium differentiated cultures which showed a corresponding increase in connexin 43 mRNA, a major component of keratinocyte hemichannels. The known connexin hemichannel inhibitors 1-octanol and carbenoxolone both significantly reduced air-stimulated ATP release, as did two drugs traditionally used as ABC transporter inhibitors (glibenclamide and verapamil). These same 4 inhibitors also prevented an increase in the uptake of a connexin permeable dye induced by air exposure, confirming that connexin hemichannels are open during air-stimulated ATP release. In contrast, activity of the MDR1 ABC transporter was reduced by air exposure and the drugs that inhibited air-stimulated ATP release had differential effects on this transporter. These results indicate that air exposure elicits non-vesicular release of ATP from keratinocytes through connexin hemichannels and that drugs used to target connexin hemichannels and ABC transporters may cross-inhibit. Connexins represent a novel, peripheral target for the treatment of chronic pain and dermatological disease.

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Section: Resultsmentioning

confidence: 99%

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

et al. 2013

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“…p38 was previously shown to activate CFTRdependent chloride secretion in response to flagellin stimulation, which is necessary for efficient water transport and mucus hydration (32). Interestingly, gap junctions were also involved in CFTR function and airway surface liquid hydration (12). Thus, Cx43 induction by PAO1 can be considered as a component of the response of airway epithelial cells to innate immune activation, leading to a regulated increase in gap junctional intercellular communication.…”

Section: Discussionmentioning

confidence: 99%

“…Data were sampled using the interface DI-720 (DataQ Instruments) and recorded/displayed using the Acquire & Analyze software 2.3 (Physiological Instruments). CFTR-dependent Isc was evoked by basolateral application of 10 mM trypsin (Sigma-Aldrich), as previously reported (12).…”

Section: Ussing Chambermentioning

confidence: 99%

“…We have recently shown in the human airway epithelial Calu-3 cell line grown under polarized conditions that Cx43-made gap junction channels coordinate a signaling network to activate CFTR and modulate airway surface liquid volume (12). Because airway surface liquid homeostasis is a defense mechanism against infection, we sought to investigate innate immune recognition and epithelial responses at the level of Cx43 in polarized Calu-3 cells infected with PAO1, a laboratory strain of P. aeruginosa.…”

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confidence: 99%

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Pseudomonas aeruginosa–Induced Apoptosis in Airway Epithelial Cells Is Mediated by Gap Junctional Communication in a JNK-Dependent Manner

Losa

Köhler

Bellec

et al. 2014

The Journal of Immunology

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Chronic infection and inflammation of the airways is a hallmark of cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The response of the CF airway epithelium to the opportunistic pathogen Pseudomonas aeruginosa is characterized by altered inflammation and apoptosis. In this study, we examined innate immune recognition and epithelial responses at the level of the gap junction protein connexin43 (Cx43) in polarized human airway epithelial cells upon infection by PAO1. We report that PAO1 activates cell surface receptors to elicit an intracellular signaling cascade leading to enhancement of gap junctional communication. Expression of Cx43 involved an opposite regulation exerted by JNK and p38 MAPKs. PAO1-induced apoptosis was increased in the presence of a JNK inhibitor, but latter effect was prevented by lentiviral expression of a Cx43-specific short hairpin RNA. Moreover, we found that JNK activity was upregulated by pharmacological inhibition of CFTR in Calu-3 cells, whereas correction of a CF airway cell line (CF15 cells) by adenoviral expression of CFTR reduced the activation of this MAPK. Interestingly, CFTR inhibition in Calu-3 cells was associated with decreased Cx43 expression and reduced apoptosis. These results indicate that Cx43 expression is a component of the response of airway epithelial cells to innate immune activation by regulating the survival/apoptosis balance. Defective CFTR could alter this equilibrium with deleterious consequences on the CF epithelial response to P. aeruginosa

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“…Indeed, host defense and efficient mucociliary clearance is achieved by the stimulation of chloride transport and subsequent regulation of airway surface hydration. Other mediators have been reported to play a role in epithelial transport, including pro-inflammatory mediators, such as prostaglandins, leukotrienes and interferon gamma [24][25][26] as well as pro-resolution mediators 27 . In other models, such as the colon adenocarcinoma-derived cell line T84, the same treatment reduced CFTR expression and function 6 .…”

Section: Discussionmentioning

confidence: 99%

An unexpected effect of TNF-α on F508del-CFTR maturation and function

et al. 2015

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Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( which encodes a CFTR), cAMP-dependent Cl channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in

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Prostaglandin E₂ Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Activity and Airway Surface Liquid Volume Requires Gap Junctional Communication

Cited by 25 publications

References 40 publications

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

Pseudomonas aeruginosa–Induced Apoptosis in Airway Epithelial Cells Is Mediated by Gap Junctional Communication in a JNK-Dependent Manner

An unexpected effect of TNF-α on F508del-CFTR maturation and function

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Prostaglandin E2 Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Activity and Airway Surface Liquid Volume Requires Gap Junctional Communication

Cited by 25 publications

References 40 publications

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

Air-Stimulated ATP Release from Keratinocytes Occurs through Connexin Hemichannels

Pseudomonas aeruginosa–Induced Apoptosis in Airway Epithelial Cells Is Mediated by Gap Junctional Communication in a JNK-Dependent Manner

An unexpected effect of TNF-α on F508del-CFTR maturation and function

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Prostaglandin E₂ Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Activity and Airway Surface Liquid Volume Requires Gap Junctional Communication