Andrographolide exerted its antimicrobial effects by upregulation of human β-defensin-2 induced through p38 MAPK and NF-κB pathway in human lung epithelial cells

2012 ◽  
Vol 90 (5) ◽  
pp. 647-653 ◽  
Author(s):  
Zhen-Jun Shao ◽  
Xiao-Wei Zheng ◽  
Ting Feng ◽  
Juan Huang ◽  
Jian Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
P38 Mapk ◽  
Nuclear Factor Κb ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Antimicrobial Effects ◽  
Reverse Transcription Pcr ◽  
Lung Epithelial ◽  
Mitogen Activated Protein

Andrographis paniculata (Burm. f) Nees is a traditional herbal medicine for the treatment of infection and inflammation in China. Andrographolide (andro) is one of the major components. Human β-defensin-2 (hBD-2) is an inducible antimicrobial peptide that plays an important role in innate immunity. The present study aimed to investigate the effect of andro on upregulation of hBD-2 and the key signaling pathways involved in andro-induced hBD-2 expression. Real-time reverse transcription – PCR and Western blot assays showed that andro (1.0–10 µmol/L) can upregulate the expression of hBD-2 in a dose-dependent manner. Further studies suggested that hBD-2 mRNA and protein expression in responsive to andro were attenuated by pretreatment with SB203580 (an inhibitor of p38 mitogen-activated protein kinase (p38 MAPK)), MG-132 (an inhibitor of nuclear factor κB (NF-κB)), and an NF-κB activator inhibitor, but not by an inhibitor of ERK (PD98059) or by an inhibitor of JNK(SP600125). Moreover, we found that a second p38 MAPK inhibitor (SB202190) significantly blocked andro-mediated hBD-2 induction in SPC-A-1 lung epithelial cells. Finally, the p-c-Jun transcription factor activity assay also showed that AP-1 activity was induced by andro compared with the untreated group. We conclude that andro may exert its antimicrobial effects by upregulating the expression of hBD-2 through the p38 MAPK and NF-κB pathway.

TNF-α inhibits SP-A gene expression in lung epithelial cells via p38 MAPK

2002 ◽  
Vol 283 (2) ◽  
pp. L418-L427 ◽  
Author(s):  
Olga L. Miakotina ◽  
Jeanne M. Snyder
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tnf Α ◽  
Lung Epithelial

Surfactant protein A (SP-A), the major lung surfactant-associated protein, mediates local defense against pathogens and modulates inflammation in the alveolus. Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, inhibits SP-A gene expression in lung epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase pathway, i.e., wortmannin, LY-294002, and rapamycin, did not block the inhibitory effects of TNF-α on SP-A mRNA levels. An inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, PD-98059, was also ineffective. PD-169316 and SB-203580, inhibitors of p38 MAPK, blocked the TNF-α-mediated inhibition of SP-A mRNA levels. TNF-α increased the phosphorylation of p38 MAPK within 15 min. Anisomycin, an activator of p38 MAPK, increased p38 MAPK phosphorylation and decreased SP-A mRNA levels in a dose-dependent manner. Finally, TNF-α increased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNF-α downregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.

TNF up-regulates ST3GAL4 and sialyl-Lewisx expression in lung epithelial cells through an intronic ATF2-responsive element

2016 ◽  
Vol 474 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Florent Colomb ◽  
Marie-Ange Krzewinski-Recchi ◽  
Agata Steenackers ◽  
Audrey Vincent ◽  
Anne Harduin-Lepers ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mapk Signaling ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Sialyl Lewisx ◽  
Extracellular Signal ◽  
Potential Binding ◽  
Lung Epithelial ◽  
Mitogen Activated Protein ◽  
Responsive Element

We have previously shown that tumor necrosis factor (TNF) induced the up-regulation of the sialyltransferase gene ST3GAL4 (α2,3-sialyltransferase gene) BX transcript through mitogen- and stress-activated kinase 1/2 (MSK1/2), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. This up-regulation resulted in sialyl-Lewisx (sLex) overexpression on high-molecular-weight glycoproteins in inflamed airway epithelium and increased the adhesion of Pseudomonas aeruginosa PAO1 and PAK strains to lung epithelial cells. In the present study, we describe a TNF-responsive element in an intronic region of the ST3GAL4 gene, whose TNF-dependent activity is repressed by ERK/p38 and MSK1/2 inhibitors. This TNF-responsive element contains potential binding sites for ETS1 and ATF2 transcription factors related to TNF signaling. We also show that ATF2 is involved in TNF responsiveness, as well as in TNF-induced ST3GAL4 BX transcript and sLex overexpression in A549 lung epithelial cells. Moreover, we show that TNF induces the binding of ATF2 to the TNF-responsive element. Altogether, these data suggest that ATF2 could be a potential target to prevent inflammation-induced P. aeruginosa binding in the lung of patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis.

Neutrophil elastase induces IL-8 synthesis by lung epithelial cells via the mitogen-activated protein kinase pathway

2004 ◽  
Vol 11 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Hao-Cheng Chen ◽  
Horng-Chyuan Lin ◽  
Chien-Ying Liu ◽  
Chun-Hua Wang ◽  
Tritium Hwang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Neutrophil Elastase ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Lung Epithelial ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

scholarly journals Phosphothreonine Lyase Promotes p65 Degradation in a Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1-Dependent Manner

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Mingyu Hou ◽  
Wenhui Wang ◽  
Feizi Hu ◽  
Yuanxing Zhang ◽  
Dahai Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pathogenic Bacteria ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Content Type ◽  
Catalytic Active Site ◽  
Mitogen Activated Protein

ABSTRACT Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.

scholarly journals Cytotoxic Effects of Air Freshener Biocides in Lung Epithelial Cells

2013 ◽  
Vol 8 (9) ◽  
pp. 1934578X1300800
Author(s):  
Jung-Taek Kwon ◽  
Mimi Lee ◽  
Gun-Baek Seo ◽  
Hyun-Mi Kim ◽  
Ilseob Shim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Lung Epithelial Cells ◽  
Ros Generation ◽  
Dependent Manner ◽  
Cytotoxic Effects ◽  
Lung Epithelial ◽  
Dose Dependent ◽  
A549 Lung

This study evaluated the cytotoxicity of mixtures of citral (CTR) and either benzisothiazolinone (BIT, Mix-CTR-BIT) or triclosan (TCS, Mix-CTR-TCS) in human A549 lung epithelial cells. We investigated the effects of various mix ratios of these common air freshener ingredients on cell viability, cell proliferation, reactive oxygen species (ROS) generation, and DNA damage. Mix-CTR-BIT and Mix-CTR-TCS significantly decreased the viability of lung epithelial cells and inhibited cell growth in a dose-dependent manner. In addition, both mixtures increased ROS generation, compared to that observed in control cells. In particular, cell viability, growth, and morphology were affected upon increase in the proportion of BIT or TCS in the mixture. However, comet analysis showed that treatment of cells with Mix-CTR-BIT or Mix-CTR-TCS did not increase DNA damage. Taken together, these data suggested that increasing the content of biocides in air fresheners might induce cytotoxicity, and that screening these compounds using lung epithelial cells may contribute to hazard assessment.

Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells

2006 ◽  
Vol 291 (3) ◽  
pp. L487-L495 ◽  
Author(s):  
Ian B. Copland ◽  
Denis Reynaud ◽  
Cecil Pace-Asciak ◽  
Martin Post
Keyword(s):  
Mechanical Ventilation ◽  
Arachidonic Acid ◽  
Epithelial Cells ◽  
Fetal Lung ◽  
Lung Epithelial Cells ◽  
Cyclic Stretch ◽  
Mitogen Activated Protein Kinase ◽  
Lung Epithelial ◽  
The Media ◽  
Cox 2

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.

p38 mitogen-activated protein kinase inhibits calcium-dependent chloride secretion in T84 colonic epithelial cells

2003 ◽  
Vol 284 (2) ◽  
pp. C339-C348 ◽  
Author(s):  
Stephen J. Keely ◽  
Kim E. Barrett
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Muscarinic Agonist ◽  
Colonic Epithelial Cells ◽  
Mitogen Activated Protein ◽  
Intracellular Ca ◽  
Sb 203580

We have previously shown that Ca2+-dependent Cl−secretion across intestinal epithelial cells is limited by a signaling pathway involving transactivation of the epidermal growth factor receptor (EGFR) and activation of ERK mitogen-activated protein kinase (MAPK). Here, we have investigated a possible role for p38 MAPK in regulation of Ca2+-dependent Cl− secretion. Western blot analysis of T84 colonic epithelial cells revealed that the muscarinic agonist carbachol (CCh; 100 μM) stimulated phosphorylation and activation of p38 MAPK. The p38 inhibitor SB-203580 (10 μM) potentiated and prolonged short-circuit current ( I sc) responses to CCh across voltage-clamped T84 cells to 157.4 ± 6.9% of those in control cells ( n = 21; P < 0.001). CCh-induced p38 phosphorylation was attenuated by the EGFR inhibitor tyrphostin AG-1478 (0.1 nM–10 μM) and by the Src family kinase inhibitor PP2 (20 nM–2 μM). The effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 μM), which specifically elevates intracellular Ca2+, and were abolished by the Ca2+ chelator BAPTA-AM (20 μM), implying a role for intracellular Ca2+ in mediating p38 activation. SB-203580 (10 μM) potentiated I sc responses to TG to 172.4 ± 18.1% of those in control cells ( n= 18; P < 0.001). When cells were pretreated with SB-203580 and PD-98059 to simultaneously inhibit p38 and ERK MAPKs, respectively, I sc responses to TG and CCh were significantly greater than those observed with either inhibitor alone. We conclude that Ca2+-dependent agonists stimulate p38 MAPK in T84 cells by a mechanism involving intracellular Ca2+, Src family kinases, and the EGFR. CCh-stimulated p38 activation constitutes a similar, but distinct and complementary, antisecretory signaling pathway to that of ERK MAPK.

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