Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (overdistension of the lung) triggers a proinflammatory response. Along with cytokines, inflammatory mediators such as bioactive lipids are involved in the regulation of the inflammatory response. The arachidonic acid pathway is a key source of bioactive lipid mediators, including prostanoids. Although ventilation has been shown to influence the production of prostanoids in the lung, the mechanotransduction pathways are unknown. Herein, we established that cyclic stretch of fetal lung epithelial cells, but not fibroblasts, can evoke an extremely sensitive, rapid alteration in eicosanoid metabolism through a cyclooxygenase (COX)-2 dependent mechanism. Cyclic stretch significantly increased PGI2, PGF2α, PGD2, PGE2, and thromboxane B2 levels in the media of epithelial cells, but did not alter leukotriene B4 or 12-hydroxyeicosatetraenoic acid levels. Inhibition of COX-2, but not COX-1, attenuated the cyclic stretch-induced PG increase in the media, suggesting that cyclic stretch primarily affected PG synthesis. Substrate (free arachidonic acid) availability for PG generation was increased because of a cyclic stretch-induced activation of cytosolic phospholipase A2 (cPLA2) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA2 and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.

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MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00051.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. L81-L87 ◽

Cited By ~ 32

Author(s):

Sharmistha Bhattacharyya ◽

Usha Gutti ◽

Jose Mercado ◽

Chad Moore ◽

Harvey B. Pollard ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Protein Expression ◽

Signaling Pathways ◽

Mrna Stability ◽

Mapk Signaling ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

The Stability ◽

Mapk Signaling Pathways

Cystic fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung, caused by mutations in the CFTR gene. IL-8 and other proinflammatory mediators are elevated in the CF airway, and the immediate mechanism may depend on disease-specific stabilization of IL-8 mRNA in CF lung epithelial cells. MAPK signaling pathways impact directly on IL-8 protein expression in CF cells, and we have hypothesized that the mechanism may also involve stabilization of the IL-8 mRNA. To test this hypothesis, we have examined the effects of pharmacological and molecular inhibitors of p38, and downstream MK2, ERK1/2, and JNK, on stability of IL-8 mRNA in CF lung epithelial cells. We previously showed that tristetraprolin (TTP) was constitutively low in CF and that raising TTP destabilized the IL-8 mRNA. We therefore also tested these effects on CF lung epithelial cells stably expressing TTP. TTP binds to AU-rich elements in the 3′-UTR of the IL-8 mRNA. We find that inhibition of p38 and ERK1/2 reduces the stability of IL-8 mRNA in parental CF cells. However, neither intervention further lowers TTP-dependent destabilization of IL-8 mRNA. By contrast, inhibition of the JNK-2 pathway has no effect on IL-8 mRNA stability in parental CF cell, but rather increases the stability of the message in cells expressing high levels of TTP. However, we find that inhibition of ERK1/2 or p38 leads to suppression of the effect of JNK-2 inhibition on IL-8 mRNA stability. These data thus lend support to our hypothesis that constitutive MAPK signaling and proteasomal activity might also contribute, along with aberrantly lower TTP, to the proinflammatory phenotype in CF lung epithelial cells by increasing IL-8 mRNA stability and IL-8 protein expression.

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COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

Asia-pacific Journal of Multimedia services convergent with Art Humanities and Sociology ◽

10.14257/ajmahs.2017.05.18 ◽

2017 ◽

Vol 7 (5) ◽

pp. 467-474

Author(s):

Chung Mu Park

Keyword(s):

Epithelial Cells ◽

Phorbol Ester ◽

Human Lung ◽

Inhibitory Effect ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Cox 2 ◽

Human Lung Epithelial Cells

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Phloretin inhibits interleukin-1β-induced COX-2 and ICAM-1 expression through inhibition of MAPK, Akt, and NF-κB signaling in human lung epithelial cells

Food & Function ◽

10.1039/c5fo00149h ◽

2015 ◽

Vol 6 (6) ◽

pp. 1960-1967 ◽

Cited By ~ 29

Author(s):

Wen-Chung Huang ◽

Shu-Ju Wu ◽

Rong-Syuan Tu ◽

You-Rong Lai ◽

Chian-Jiun Liou

Keyword(s):

Epithelial Cells ◽

Proinflammatory Cytokine ◽

Human Lung ◽

Lung Epithelial Cells ◽

Interleukin 1Β ◽

Lung Epithelial ◽

Cox 2 ◽

Human Lung Epithelial Cells

Phloretin inhibited proinflammatory cytokine and COX-2 expression in IL-1β-activated human lung epithelial cells.

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Oncogenic K-Ras Regulates Proliferation and Cell Junctions in Lung Epithelial Cells through Induction of Cyclooxygenase-2 and Activation of Metalloproteinase-9

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0732 ◽

2009 ◽

Vol 20 (3) ◽

pp. 791-800 ◽

Cited By ~ 35

Author(s):

Xue-Qing Wang ◽

Howard Li ◽

Vicki Van Putten ◽

Robert A. Winn ◽

Lynn E. Heasley ◽

...

Keyword(s):

Epithelial Cells ◽

Biological Effects ◽

Three Dimensional ◽

Lung Epithelial Cells ◽

Cell Junctions ◽

Prostaglandin E ◽

Erk Activation ◽

Lung Epithelial ◽

Cox 2 ◽

E Cadherin

Expression of oncogenic K-Ras is frequently observed in non–small-cell lung cancer. However, oncogenic K-Ras is not sufficient to transform lung epithelial cells and requires collaborating signals that have not been defined. To examine the biological effects of K-Ras in nontransformed lung epithelial cells, stable transfectants were generated in RL-65 cells, a spontaneously immortalized lung epithelial cell line. Expression of K-Ras resulted in extracellular signal-regulated kinase (ERK) activation, which mediated induction of cyclooxygenase (COX)-2 and increased prostaglandin E2 production. Epithelial cells expressing oncogenic K-Ras showed increased proliferation in two- and three-dimensional tissue culture and delayed formation of hollow acinar structures in three-dimensional matrigel cultures. These affects were mediated through COX-2–dependent activation of β-catenin signaling and inhibition of apoptosis. ERK activation also led to induction of metalloproteinase (MMP)-9 and cleavage of E-cadherin at two specific sites. This resulted in partial disruption of adherens junctions as determined by decreased transepithelial resistance (TER), and disruption of E-cadherin/β-catenin interactions. An MMP-9 inhibitor reversed the decrease in TER and inhibited β-catenin signaling. These data indicate that although expression of oncogenic K-Ras does not transform lung epithelial cells, it alters the phenotype of the cells by increasing proliferation and decreasing cell–cell contacts characteristic of epithelial cells.

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