Expression and localization of COX-2 in human airways and cultured airway epithelial cells

Interleukin (IL)-8, the C-X-C chemokine, is a potent neutrophil chemoattractant that has been implicated in a number of inflammatory airway diseases such as cystic fibrosis. Here we tested the hypothesis that bradykinin, an inflammatory mediator and chloride secretagogue, would increase IL-8 generation in airway epithelial cells through autocrine generation of endogenous prostanoids. Bradykinin increased IL-8 generation in both a non-cystic fibrosis (A549) and cystic fibrosis epithelial cell line (CFTE29[Formula: see text]) that was inhibited by the nonselective cyclooxygenase (COX) inhibitor indomethacin and the COX-2 selective inhibitor NS-398. COX-2 was the only isoform of COX expressed in both cell lines. Furthermore, the COX substrate arachidonic acid and exogenous prostaglandin E2 both increased IL-8 release in A549 cells. These results suggest that bradykinin may contribute to neutrophilic inflammation in the airway by generation of IL-8 from airway epithelial cells. The dependence of this response on endogenous production of prostanoids by COX-2 suggests that selective COX-2 inhibitors may have a role in the treatment of airway diseases characterized by neutrophilic inflammation such as cystic fibrosis or chronic obstructive pulmonary disease.

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Faculty Opinions recommendation of Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725538413.793514986 ◽

2016 ◽

Author(s):

James Martin

Keyword(s):

Smooth Muscle ◽

Epithelial Cells ◽

Smooth Muscle Cells ◽

Airway Smooth Muscle ◽

Airway Epithelial Cells ◽

Airway Smooth Muscle Cells ◽

Airway Epithelial ◽

Vegf Expression ◽

Human Airway Smooth Muscle ◽

Cox 2

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Tollip Inhibits ST2 Signaling in Airway Epithelial Cells Exposed to Type 2 Cytokines and Rhinovirus

Journal of Innate Immunity ◽

10.1159/000497072 ◽

2019 ◽

Vol 12 (1) ◽

pp. 103-115 ◽

Cited By ~ 4

Author(s):

Azzeddine Dakhama ◽

Reem Al Mubarak ◽

Nicole Pavelka ◽

Dennis Voelker ◽

Max Seibold ◽

...

Keyword(s):

Epithelial Cells ◽

Molecular Mechanisms ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Proinflammatory Response ◽

Type 2 Cytokines ◽

Cytokine Milieu ◽

Human Airways

The negative immune regulator Tollip inhibits the proinflammatory response to rhinovirus (RV) infection, a contributor to airway neutrophilic inflammation and asthma exacerbations, but the underlying molecular mechanisms are poorly understood. Tollip may inhibit IRAK1, a signaling molecule downstream of ST2, the receptor of IL-33. This study was carried out to determine whether Tollip downregulates ST2 signaling via inhibition of IRAK1, but promotes soluble ST2 (sST2) production, thereby limiting excessive IL-8 production in human airway epithelial cells during RV infection in a type 2 cytokine milieu (e.g., IL-13 and IL-33 stimulation). Tollip- and IRAK1-deficient primary human tracheobronchial epithelial (HTBE) cells and Tollip knockout (KO) HTBE cells were generated using the shRNA knockdown and CRISPR/Cas9 approaches, respectively. Cells were stimulated with IL-13, IL-33, and/or RV16. sST2, activated IRAK1, and IL-8 were measured. A Tollip KO mouse model was utilized to test if Tollip regulates the airway inflammatory response to RV infection in vivo under IL-13 and IL-33 treatment. Following IL-13, IL-33, and RV treatment, Tollip-deficient (vs. -sufficient) HTBE cells produced excessive IL-8, accompanied by decreased sST2 production but increased IRAK1 activation. IL-8 production following IL-13/IL-33/RV exposure was markedly attenuated in IRAK1-deficient HTBE cells, as well as in Tollip KO HTBE cells treated with an IRAK1 inhibitor or a recombinant sST2 protein. Tollip KO (vs. wild-type) mice developed exaggerated airway neutrophilic responses to RV in the context of IL-13 and IL-33 treatment. Collectively, these data demonstrate that Tollip restricts excessive IL-8 production in type 2 cytokine-exposed human airways during RV infection by promoting sST2 production and inhibiting IRAK1 activation. sST2 and IRAK1 may be therapeutic targets for attenuating excessive neutrophilic airway inflammation in asthma, especially during RV infection.

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Parainfluenza virus infection enhances NSAIDs–induced inhibition of PGE2 generation and COX-2 expression in human airway epithelial cells

Advances in Medical Sciences ◽

10.1016/j.advms.2019.04.004 ◽

2019 ◽

Vol 64 (2) ◽

pp. 338-343 ◽

Cited By ~ 6

Author(s):

Anna Lewandowska-Polak ◽

Małgorzata Brauncajs ◽

Marzanna Jarzębska ◽

Małgorzata Pawełczyk ◽

Marcin Kurowski ◽

...

Keyword(s):

Epithelial Cells ◽

Virus Infection ◽

Airway Epithelial Cells ◽

Parainfluenza Virus ◽

Airway Epithelial ◽

Human Airway ◽

Cox 2 ◽

Human Airway Epithelial Cells

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Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPARγ agonists: evidence for disparate functional effects which are independent of NF-κB and PPARγ

Cellular Signalling ◽

10.1016/j.cellsig.2004.12.002 ◽

2005 ◽

Vol 17 (9) ◽

pp. 1098-1110 ◽

Cited By ~ 21

Author(s):

K PATEL ◽

K WRIGHT ◽

P WHITTAKER ◽

P CHAKRAVARTY ◽

M WATSON ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Differential Modulation ◽

Pparγ Agonists ◽

Cox 2

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Fisetin suppresses cigarette smoke extract-induced epithelial to mesenchymal transition of airway epithelial cells through regulating COX-2/MMPs/β-catenin pathway

Chemico-Biological Interactions ◽

10.1016/j.cbi.2021.109771 ◽

2021 ◽

pp. 109771

Author(s):

Hina Agraval ◽

Jiten R. Sharma ◽

Nutan Prakash ◽

Umesh C.S. Yadav

Keyword(s):

Epithelial Cells ◽

Cigarette Smoke ◽

Epithelial To Mesenchymal Transition ◽

Cigarette Smoke Extract ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Mesenchymal Transition ◽

Cox 2

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Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00390.2014 ◽

2015 ◽

Vol 309 (3) ◽

pp. L237-L249 ◽

Cited By ~ 19

Author(s):

Karl Deacon ◽

Alan J. Knox

Keyword(s):

Smooth Muscle ◽

Epithelial Cells ◽

Smooth Muscle Cells ◽

Airway Smooth Muscle ◽

Airway Epithelial Cells ◽

Airway Smooth Muscle Cells ◽

Airway Epithelial ◽

Human Airway Smooth Muscle ◽

Cox 2 ◽

Stimulation Of

Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production.

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Neutrophil elastase stimulates human airway epithelial cells to produce PGE2 through activation of p44/42 MAPK and upregulation of cyclooxygenase-2

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00182.2002 ◽

2003 ◽

Vol 285 (4) ◽

pp. L925-L930 ◽

Cited By ~ 17

Author(s):

Diahn-Warng Perng ◽

Yu-Chung Wu ◽

Mei-Chuan Tsai ◽

Ching-Ping Lin ◽

Wen-Hu Hsu ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelium ◽

Neutrophil Elastase ◽

Map Kinases ◽

Kinase Inhibitor ◽

Housekeeping Gene ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Cox 2 ◽

Air Liquid Interface

The responses of airway epithelium following exposure to neutrophil elastase (NE) were investigated. Human bronchial epithelial cells were explanted on insert surfaces of a modified air-liquid interface culture system to which NE was added to stimulate epithelial cells. PGE2 release significantly increased within 10 min of incubation with NE and peaked 3 h after NE (20 μg/ml) stimulation. This action required proteolytic activity as α1-antitrypsin blocked NE-induced PGE2 release. The production of PGE2 was also inhibited by indomethacin; a selective cyclooxygenase (COX)-2 inhibitor, celecoxib; and dexamethasone. Moreover, the mRNA expression for COX-2 relative to that for a housekeeping gene was approximately eightfold that of the unstimulated cells. Dexamethasone inhibited COX-2 gene transcription. We further observed that NE-induced PGE2 release involved activation of p44/42, but not p38, MAP kinases. Such p44/42 MAP kinases were rapidly phosphorylated, with the concentration of phosphorylated p44/42 MAP kinases peaking at 10 min after stimulation and declining in culture at 90 min. The specific p44/42 MAP kinase inhibitor UO126 completely blocked p44/42 phosphorylation and, subsequently, PGE2 production. The airway epithelium may play important bronchoprotective and immunomodulatory roles in chronic neutrophilic inflammation.

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