scholarly journals Ets-1 is a negative regulator of Th17 differentiation

2007 ◽  
Vol 204 (12) ◽  
pp. 2825-2835 ◽  
Author(s):  
Jacques Moisan ◽  
Roland Grenningloh ◽  
Estelle Bettelli ◽  
Mohamed Oukka ◽  
I-Cheng Ho
Keyword(s):  
Th17 Cells ◽  
Inhibitory Effect ◽  
Airway Epithelial Cells ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Th Cells ◽  
Th17 Differentiation ◽  
High Level

IL-17 is a proinflammatory cytokine that plays a role in the clearance of extracellular bacteria and contributes to the pathology of many autoimmune and allergic conditions. IL-17 is produced mainly by a newly characterized subset of T helper (Th) cells termed Th17. Although the role of Th17 cells in the pathology of autoimmune diseases is well established, the transcription factors regulating the differentiation of Th17 cells remain poorly characterized. We report that Ets-1–deficient Th cells differentiated more efficiently to Th17 cells than wild-type cells. This was attributed to both low IL-2 production and increased resistance to the inhibitory effect of IL-2 on Th17 differentiation. The resistance to IL-2 suppression was caused by a defect downstream of STAT5 phosphorylation, but was not caused by a difference in the level of RORγt. Furthermore, Ets-1–deficient mice contained an abnormally high level of IL-17 transcripts in their lungs and exhibited increased mucus production by airway epithelial cells in an IL-17–dependent manner. Based on these observations, we report that Ets-1 is a negative regulator of Th17 differentiation.

Effects of dexamethasone on Muc5ac mucin production by primary airway goblet cells

2005 ◽  
Vol 288 (1) ◽  
pp. L52-L60 ◽  
Author(s):  
Wenju Lu ◽  
Erik P. Lillehoj ◽  
K. Chul Kim
Keyword(s):  
A549 Cells ◽  
Airway Epithelial Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Mucin Production ◽  
Proinflammatory Mediators ◽  
A Cell ◽  
The Stability

Mucus hypersecretion associated with airway inflammation is reduced by glucocorticoids. Two mechanisms of glucocorticoid-mediated inhibition of mucus production have been proposed, direct inhibition of mucus production by airway epithelial cells and indirectly through inhibition of proinflammatory mediators that stimulate mucus production. In this study, we examined the effect of dexamethasone (DEX) on mRNA expression and synthesis of MUC5AC by A549 human lung adenocarcinoma cells as well as Muc5ac and total high-molecular-weight (HMW) mucins by primary rat tracheal surface epithelial (RTSE) cells. Our results showed that in primary RTSE cells, DEX 1) dose dependently suppressed Muc5ac mRNA levels, but the levels of cellular Muc5ac protein and HMW mucins were unaffected; 2) did not affect constitutive or UTP-stimulated mucin secretion; 3) enhanced the translation of Muc5ac; and 4) increased the stability of intracellular Muc5ac protein by a mechanism other than the inhibition of the proteasomal degradation. In A549 cells, however, DEX suppressed both MUC5AC mRNA levels and MUC5AC protein secretion in a dose-dependent manner. We conclude that whereas DEX inhibits the levels of Muc5ac mRNA in primary RTSE cells, the levels of Muc5ac protein remain unchanged as a consequence of increases in both translation and protein stability. Interestingly, some of the effects of DEX were opposite in a cell line.

scholarly journals Neutrophil Extracellular DNA Traps Induce Autoantigen Production by Airway Epithelial Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Youngwoo Choi ◽  
Le Duy Pham ◽  
Dong-Hyun Lee ◽  
Ga-Young Ban ◽  
Ji-Ho Lee ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tissue Transglutaminase ◽  
Airway Epithelial Cells ◽  
Extracellular Dna ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Concentration Dependent Manner ◽  
Autoantibody Production ◽  
High Level ◽  
Extracellular Dna Traps

The hypothesis of autoimmune involvement in asthma has received much recent interest. Autoantibodies, such as anti-cytokeratin (CK) 18, anti-CK19, and anti-α-enolase antibodies, react with self-antigens and are found at high levels in the sera of patients with severe asthma (SA). However, the mechanisms underlying autoantibody production in SA have not been fully determined. The present study was conducted to demonstrate that neutrophil extracellular DNA traps (NETs), cytotoxic molecules released from neutrophils, are a key player in the stimulation of airway epithelial cells (AECs) to produce autoantigens. This study showed that NETs significantly increased the intracellular expression of tissue transglutaminase (tTG) but did not affect that of CK18 in AECs. NETs induced the extracellular release of both tTG and CK18 in a concentration-dependent manner. Moreover, NETs directly degraded intracellularα-enolase into small fragments. However, antibodies against neutrophil elastase (NE) or myeloperoxidase (MPO) attenuated the effects of NETs on AECs. Furthermore, each NET isolated from healthy controls (HC), nonsevere asthma (NSA), and SA had different characteristics. Taken together, these findings suggest that AECs exposed to NETs may exhibit higher autoantigen production, especially in SA. Therefore, targeting of NETs may represent a new therapy for neutrophilic asthma with a high level of autoantigens.

scholarly journals Deacetylation of p53 induces autophagy by suppressing Bmf expression

2013 ◽  
Vol 201 (3) ◽  
pp. 427-437 ◽  
Author(s):  
Amelia U. Contreras ◽  
Yohannes Mebratu ◽  
Monica Delgado ◽  
Gilbert Montano ◽  
Chien-an A. Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Messenger Rna ◽  
Histone Deacetylase Inhibitors ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Independent Manner ◽  
Rich Domain ◽  
Ifn Γ

Interferon γ (IFN-γ)–induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN-γ on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-γ down-regulated expression of the BH3 domain-only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death–stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-γ did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-γ–induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53’s proline-rich domain. Suppression of Bmf facilitated IFN-γ–induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf−/− but not in bmf+/+ cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy.

Participation of MAPK, PKA and PP2A in the regulation of MPF activity in Bufo arenarum oocytes

Zygote ◽  
2010 ◽  
Vol 19 (2) ◽  
pp. 181-189 ◽  
Author(s):  
G. Sánchez Toranzo ◽  
F. Bonilla ◽  
M.C. Gramajo Bühler ◽  
M.I. Bühler
Keyword(s):  
Mapk Pathway ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
Mapk Cascade ◽  
Dependent Manner ◽  
Cdc25 Phosphatase ◽  
Signalling Molecules ◽  
Bufo Arenarum ◽  
Phosphatase 2A ◽  
Dose Dependent

SummaryThe objectives of the present paper were to study the involvement and possible interactions of both cAMP-PKA and protein phosphatases in Bufo arenarum oocyte maturation and to determine if these pathways are independent or not of the MAP kinase (MAPK) cascade. Our results indicated that the inhibition of PKA by treatment with H-89, an inhibitor of the catalytic subunit of PKA, was capable of inducing GVBD in a dose-dependent manner by a pathway in which Cdc25 phosphatase but not the MAPK cascade is involved. The injection of 50 nl of H-89 10 μM produced GVBD percentages similar to those obtained with treatment with progesterone. In addition, the assays with okadaic acid (OA), a PP2A inhibitor, significantly enhanced the percentage of oocytes that resumed meiosis by a signal transducing pathway in which the activation of the MEK–MAPK pathway is necessary, but in which Cdc25 phosphatase was not involved. Treatment with H-89, was able to overcome the inhibitory effect of PKA on GVBD; however, the inhibition of Cdc25 activity with NaVO3 was able to overcome the induction of GVBD by H-89. Although the connections between PKA and other signalling molecules that regulate oocytes maturation are still unclear, our results suggest that phosphatase Cdc25 may be the direct substrate of PKA. In Xenopus oocytes it was proposed that PP2A, a major Ser/Thr phosphatase present, is a negative regulator of Cdc2 activation. However, in Bufo arenarum oocytes, inhibition of Cdc25 with NaVO3 did not inhibit OA-induced maturation, suggesting that the target of PP2A was not the Cdc25 phosphatase. MAPK activation has been reported to be essential in Xenopus oocytes GVBD. In B. arenarum oocytes we demonstrated that the inhibition of MAPK by PD 98059 prevented the activation of MPF induced by OA, suggesting that the activation of the MAPK cascade produced an inhibition of Myt1 and, in consequence, the activation of MPF without participation of the Cdc25 phosphatase. Our results suggest that in incompetent oocytes of B. arenarum two signal transduction pathways may be involved in the control of MPF activation: (1) the inhibition of phosphatase 2A that through the MEK–MAPK pathway regulates the activity of the Myt1; and (2) the inhibition of AMPc–PKA, which affects the activity of the Cdc25 phosphatase.

scholarly journals Osteosarcoma Phenotype Is Inhibited by 3,4-Methylenedioxy-β-nitrostyrene

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Patrick J. Messerschmitt ◽  
Ashley N. Rettew ◽  
Nicholas O. Schroeder ◽  
Robert E. Brookover ◽  
Avanti P. Jakatdar ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Lines ◽  
Colony Formation ◽  
Metastatic Potential ◽  
Airway Epithelial Cells ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Human Osteoblasts ◽  
Metastatic Cell Line

β-nitrostyrene compounds, such as 3,4-methylenedioxy-β-nitrostyrene (MNS), inhibit growth and induce apoptosis in tumor cells, but no reports have investigated their role in osteosarcoma. In this study, human osteosarcoma cell families with cell lines of varying tumorigenic and metastatic potential were utilized. Scrape motility assays, colony formation assays, and colony survival assays were performed with osteosarcoma cell lines, both in the presence and absence of MNS. Effects of MNS on human osteoblasts and airway epithelial cells were assessed in monolayer cultures. MNS decreased metastatic cell line motility by 72–76% and colony formation by 95–100%. MNS consistently disrupted preformed colonies in a time-dependent and dose-dependent manner. MNS had similar effects on human osteoblasts but little effect on airway epithelial cells. An inactive analog of MNS had no detectable effects, demonstrating specificity. MNS decreases motility and colony formation of osteosarcoma cells and disrupts preformed cell colonies, while producing little effect on pulmonary epithelial cells.

scholarly journals Mechanical stretch decreases FAK phosphorylation and reduces cell migration through loss of JIP3-induced JNK phosphorylation in airway epithelial cells

2009 ◽  
Vol 297 (3) ◽  
pp. L520-L529 ◽  
Author(s):  
Leena P. Desai ◽  
Steven R. White ◽  
Christopher M. Waters
Keyword(s):  
Cell Migration ◽  
Epithelial Cells ◽  
Mechanical Strain ◽  
Mechanical Stretch ◽  
Inhibitory Effect ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Interacting Protein ◽  
Kinase Activation ◽  
Mapk Cascades

JNK is a nonreceptor kinase involved in the early events that signal cell migration after injury. However, the linkage to early signals required to initiate the migration response to JNK has not been defined in airway epithelial cells, which exist in an environment subjected to cyclic mechanical strain (MS). The present studies demonstrate that the JNK/stress-activated protein kinase-associated protein 1 (JSAP1; also termed JNK-interacting protein 3, JIP3), a scaffold factor for MAPK cascades that links JNK activation to focal adhesion kinase (FAK), are both associated and activated following mechanical injury in 16HBE14o− human airway epithelial cells and that both FAK and JIP3 phosphorylation seen after injury are decreased in cells subjected to cyclic MS. Overexpression of either wild-type (WT)-FAK or WT-JIP3 enhanced phosphorylation and kinase activation of JNK and reduced the inhibitory effect of cyclic MS. These results suggest that cyclic MS impairs signaling of cell migration after injury via a pathway that involves FAK-JIP3-JNK.

scholarly journals High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Phongthon Kanjanasirirat ◽  
Ampa Suksatu ◽  
Suwimon Manopwisedjaroen ◽  
Bamroong Munyoo ◽  
Patoomratana Tuchinda ◽  
...  
Keyword(s):  
Severe Pneumonia ◽  
Inhibitory Effect ◽  
Airway Epithelial Cells ◽  
High Content Screening ◽  
Target Cells ◽  
Airway Epithelial ◽  
Plaque Reduction Assay ◽  
Boesenbergia Rotunda ◽  
First Time ◽  
Panduratin A

AbstractSince December 2019, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused severe pneumonia, a disease named COVID-19, that became pandemic and created an acute threat to public health. The effective therapeutics are in urgent need. Here, we developed a high-content screening for the antiviral candidates using fluorescence-based SARS-CoV-2 nucleoprotein detection in Vero E6 cells coupled with plaque reduction assay. Among 122 Thai natural products, we found that Boesenbergia rotunda extract and its phytochemical compound, panduratin A, exhibited the potent anti-SARS-CoV-2 activity. Treatment with B. rotunda extract and panduratin A after viral infection drastically suppressed SARS-CoV-2 infectivity in Vero E6 cells with IC50 of 3.62 μg/mL (CC50 = 28.06 µg/mL) and 0.81 μΜ (CC50 = 14.71 µM), respectively. Also, the treatment of panduratin A at the pre-entry phase inhibited SARS-CoV-2 infection with IC50 of 5.30 µM (CC50 = 43.47 µM). Our study demonstrated, for the first time, that panduratin A exerts the inhibitory effect against SARS-CoV-2 infection at both pre-entry and post-infection phases. Apart from Vero E6 cells, treatment with this compound was able to suppress viral infectivity in human airway epithelial cells. This result confirmed the potential of panduratin A as the anti-SARS-CoV-2 agent in the major target cells in human. Since B. rotunda is a culinary herb generally grown in China and Southeast Asia, its extract and the purified panduratin A may serve as the promising candidates for therapeutic purposes with economic advantage during COVID-19 situation.

TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells

2021 ◽  
Vol 64 (1) ◽  
pp. 50-58
Author(s):  
Inês Cabrita ◽  
Roberta Benedetto ◽  
Podchanart Wanitchakool ◽  
Joana Lerias ◽  
Raquel Centeio ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Human Airway ◽  
Human Airway Epithelial Cells

scholarly journals Human Papillomavirus Type 16 E6 Activates NF-κB, Induces cIAP-2 Expression, and Protects against Apoptosis in a PDZ Binding Motif-Dependent Manner

2006 ◽  
Vol 80 (11) ◽  
pp. 5301-5307 ◽  
Author(s):  
Michael A. James ◽  
John H. Lee ◽  
Aloysius J. Klingelhutz
Keyword(s):  
Human Papillomavirus ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Pdz Domain ◽  
Airway Epithelial Cells ◽  
Binding Motif ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Transcript Accumulation ◽  
Human Telomerase Reverse Transcriptase

ABSTRACT Infection with human papillomavirus (HPV) is a critical factor in the pathogenesis of most cervical cancers and some aerodigestive cancers. The HPV E6 oncoprotein from high-risk HPV types contributes to the immortalization and transformation of cells by multiple mechanisms, including degradation of p53, transcriptional activation of human telomerase reverse transcriptase (hTERT), and degradation of several proteins containing PDZ domains. The ability of E6 to bind PDZ domain-containing proteins is independent of p53 degradation or hTERT activation but does correlate with oncogenic potential (R. A. Watson, M. Thomas, L. Banks, and S. Roberts, J. Cell Sci. 116:4925-4934, 2003) and is essential for induction of epithelial hyperplasia in vivo (M. L. Nguyen, M. M. Nguyen, D. Lee, A. E. Griep, and P. F. Lambert, J. Virol. 77:6957-6964, 2003). In this study, we found that HPV type 16 E6 was able to activate NF-κB in airway epithelial cells through the induction of nuclear binding activity of p52-containing NF-κB complexes in a PDZ binding motif-dependent manner. Transcript accumulation for the NF-κB-responsive antiapoptotic gene encoding cIAP-2 and binding of nuclear factors to the proximal NF-κB binding site of the cIAP-2 gene promoter are induced by E6 expression. Furthermore, E6 is able to protect cells from TNF-induced apoptosis. All of these E6-dependent phenotypes are dependent on the presence of the PDZ binding motif of E6. Our results imply a role for targeting of PDZ proteins by E6 in NF-κB activation and protection from apoptosis in airway epithelial cells.

scholarly journals Effects of Air Pollution-Related Heavy Metals on the Viability and Inflammatory Responses of Human Airway Epithelial Cells

2015 ◽  
Vol 34 (2) ◽  
pp. 195-203 ◽  
Author(s):  
Akiko Honda ◽  
Kenshi Tsuji ◽  
Yugo Matsuda ◽  
Tomohiro Hayashi ◽  
Wataru Fukushima ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Ambient Air ◽  
Airway Epithelial Cells ◽  
Oxidation States ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Human Airway ◽  
Human Airway Epithelial Cells

Various metals produced from human activity are ubiquitously detected in ambient air. The metals may lead to induction and/or exacerbation of respiratory diseases, but the significant metals and factors contributing to such diseases have not been identified. To compare the effects of each metal and different oxidation states of metals on human airway, we examined the viability and production of interleukin (IL)-6 and IL-8 using BEAS-2B cell line, derived from human airway epithelial cells. Airway epithelial cells were exposed to Mn2+, V4+, V5+, Cr3+, Cr6+, Zn2+, Ni2+, and Pb2+ at a concentration of 0.5, 5, 50, or 500 μmol/L for 24 hours. Mn and V decreased the cell viability in a concentration-dependent manner, and V5+ tended to have a greater effect than V4+. The Cr decreased the cell viability, and (Cr+6) at concentrations of 50 and 500 μmol/L was more toxic than (Cr+3). Zn at a concentration of 500 μmol/L greatly decreased the cell viability, whereas Ni at the same concentration increased it. Pb produced fewer changes. Mn and Ni at a concentration of 500 μmol/L induced the significant production of IL-6 and IL-8. However, most of the metals including (V+4, V+5), (Cr+3, Cr+6), Zn, and Pb inhibited the production of both IL-6 and IL-8. The present results indicate that various heavy metals have different effects on toxicity and the proinflammatory responses of airway epithelial cells, and those influences also depend on the oxidation states of the metals.

Sign in / Sign up

Export Citation Format

Share Document