Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-α via distinct NF-κB pathways in human nasal epithelial cells

Ohkuni, Tsuyoshi; Kojima, Takashi; Ogasawara, Nagahisa; Takao, Masaki; Fuchimoto, Jun; Kamekura, Ryuta; Koizumi, Jun–ichi; Ichimiya, Shingo; Murata, Masaki; Tanaka, Satoshi; Himi, Tetsuo; Sawada, Norimasa

doi:10.1016/j.taap.2010.09.023

Cited by 42 publications

(39 citation statements)

References 58 publications

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“…To the best of our knowledge, these are the first data showing dysfunction of the epithelial barrier caused by dsRNA. A recent study did not find effects of polyI:C exposure on TEER in immortalized human nasal epithelial cells, 49 which probably reflects the cell specificity of epithelial responses to dsRNA. On the other hand, polyI:C was previously shown to increase the permeability of the glomerulus 50 and marked disassembly and dysfunction of AJCs in brain microvascular endothelial cells.…”

Section: Discussionmentioning

confidence: 93%

Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells

Rezaee

Meednu

Emo

et al. 2011

Journal of Allergy and Clinical Immunology

107

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Background Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response. Objectives We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro. Methods 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy. Results PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, β-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction. Conclusions PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization.

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Section: Discussionmentioning

confidence: 93%

Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells

Rezaee

Meednu

Emo

et al. 2011

Journal of Allergy and Clinical Immunology

107

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“…JAM-A expression of the normal airway is regulated via a distinct signal transduction pathway including NF-κB [22]. The mechanisms of the overexpression of JAM-A in cancer cells, including the signal transduction pathways, are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma

et al. 2016

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“…It provokes inflammatory and interferon (IFN) responses in airway epithelial cells, similar to viral dsRNA (4,30,49). Recently, dsRNA was also shown to decrease R T in immortalized nasal epithelial cells (35), but the underlying mechanism was not elucidated. Therefore, to investigate whether dsRNA generated during RV replication contributes to the RV-induced disruption of barrier function, we used poly(I:C) (1.5 to 8 kb) as a surrogate for RV dsRNA.…”

Section: Discussionmentioning

confidence: 99%

Rhinovirus-Induced Barrier Dysfunction in Polarized Airway Epithelial Cells Is Mediated by NADPH Oxidase 1

Comstock

Ganesan

Chattoraj

et al. 2011

J Virol

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Previously, we showed that rhinovirus (RV), which is responsible for the majority of common colds, disrupts airway epithelial barrier function, as evidenced by reduced transepithelial resistance (R T ), dissociation of zona occludins 1 (ZO-1) from the tight junction complex, and bacterial transmigration across polarized cells. We also showed that RV replication is required for barrier function disruption. However, the underlying biochemical mechanisms are not known. In the present study, we found that a double-stranded RNA (dsRNA) mimetic, poly(I:C), induced tight junction breakdown and facilitated bacterial transmigration across polarized airway epithelial cells, similar to the case with RV. We also found that RV and poly(I:C) each stimulated Rac1 activation, reactive oxygen species (ROS) generation, and Rac1-dependent NADPH oxidase 1 (NOX1) activity. Inhibitors of Rac1 (NSC23766), NOX (diphenylene iodonium), and NOX1 (small interfering RNA [siRNA]) each blocked the disruptive effects of RV and poly(I:C) on R T , as well as the dissociation of ZO-1 and occludin from the tight junction complex. Finally, we found that Toll-like receptor 3 (TLR3) is not required for either poly(I:C)-or RV-induced reductions in R T . Based on these results, we concluded that Rac1-dependent NOX1 activity is required for RV-or poly(I:C)-induced ROS generation, which in turn disrupts the barrier function of polarized airway epithelia. Furthermore, these data suggest that dsRNA generated during RV replication is sufficient to disrupt barrier function.

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Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-α via distinct NF-κB pathways in human nasal epithelial cells

Cited by 42 publications

References 58 publications

Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells

Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells

Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma

Rhinovirus-Induced Barrier Dysfunction in Polarized Airway Epithelial Cells Is Mediated by NADPH Oxidase 1

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