scholarly journals IFN-γ-induced JAK/STAT, but not NF-κB, signaling pathway is insensitive to glucocorticoid in airway epithelial cells

2015 ◽  
Vol 309 (4) ◽  
pp. L348-L359 ◽  
Author(s):  
Danielle O'Connell ◽  
Belaid Bouazza ◽  
Blerina Kokalari ◽  
Yassine Amrani ◽  
Alaa Khatib ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Severe Asthma ◽  
Airway Epithelial Cells ◽  
Differential Sensitivity ◽  
Airway Epithelial ◽  
Stat Signaling ◽  
Ifn Γ ◽  
Steroid Responsiveness

Although the majority of patients with asthma are well controlled by inhaled glucocorticoids (GCs), patients with severe asthma are poorly responsive to GCs. This latter group is responsible for a disproportionate share of health care costs associated with asthma. Recent studies in immune cells have incriminated interferon-γ (IFN-γ) as a possible trigger of GC insensitivity in severe asthma; however, little is known about the role of IFN-γ in modulating GC effects in other clinically relevant nonimmune cells, such as airway epithelial cells. We hypothesized that IFN-γ-induced JAK/STAT-associated signaling pathways in airway epithelial cells are insensitive to GCs and that strategies aimed at inhibiting JAK/STAT pathways can restore steroid responsiveness. Using Western blot analysis we found that all steps of the IFN-γ-induced JAK/STAT signaling pathway were indeed GC insensitive. Transfection of cells with reporter plasmid showed IFN-γ-induced STAT1-dependent gene transcription to be also GC insensitive. Interestingly, real-time PCR analysis showed that IFN-γ-inducible genes (IIGs) were differentially affected by GC, with CXCL10 being GC sensitive and CXCL11 and IFIT2 being GC insensitive. Further investigation showed that the differential sensitivity of IIGs to GC was due to their variable dependency to JAK/STAT vs. NF-κB signaling pathways with GC-sensitive IIGs being more NF-κB dependent and GC-insensitive IIGs being more JAK/STAT dependent. Importantly, transfection of cells with siRNA-STAT1 was able to restore steroid responsiveness of GC-insensitive IIGs. Taken together, our results show the insensitivity of IFN-γ-induced JAK/STAT signaling pathways to GC effects in epithelial cells and also suggest that targeting STAT1 could restore GC responsiveness in patients with severe asthma.

Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium

2004 ◽  
Vol 287 (2) ◽  
pp. L374-L381 ◽  
Author(s):  
Shuo Zheng ◽  
Weiling Xu ◽  
Santanu Bose ◽  
Amiya K. Banerjee ◽  
S. Jaharul Haque ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Host Defense ◽  
Airway Epithelial Cells ◽  
Activator Protein 1 ◽  
Airway Epithelial ◽  
Ifn Γ ◽  
Nos2 Expression

Cystic fibrosis (CF) airway epithelial cells are more susceptible to viral infection due to impairment of the innate host defense pathway of nitric oxide (NO). NO synthase-2 (NOS2) expression is absent, and signal transducer and activator of transcription (STAT) 1 activation is reduced in CF. We hypothesized that the IFN-γ signaling pathway, which leads to NOS2 gene induction in CF airway epithelial cells, is defective. In contrast to a lack of NOS2 induction, the major histocompatibility complex class 2, an IFN-γ-regulated delayed-responsive gene, is similarly induced in CF and non-CF airway epithelial (NL) cells, suggesting an NOS2-specific defect in the IFN-γ signaling pathway. STAT1 and activator protein-1, both required for NOS2 gene expression, interact normally in CF cells. Protein inhibitor of activated STAT1 is not increased in CF cells. IFN-γ induces NOS2 expression in airway epithelial cells through an autocrine mechanism involving synthesis and secretion of IFN-γ-inducible mediator(s), which activates STAT1. Here, CF cells secrete IFN-γ-inducible factor(s), which stimulate NOS2 expression in NL cells, but not in CF cells. In contrast, IFN-γ-inducible factor(s) similarly inhibit virus in CF and NL cells. Thus autocrine activation of NOS2 is defective in CF cells, but IFN-γ induction of antiviral host defense is intact.

IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway

2006 ◽  
Vol 347 (4) ◽  
pp. 852-858 ◽  
Author(s):  
Daisuke Inoue ◽  
Muneo Numasaki ◽  
Mika Watanabe ◽  
Hiroshi Kubo ◽  
Takahiko Sasaki ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathway ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Dependent Signaling Pathway

scholarly journals Differential Sensitivity of Differentiated Epithelial Cells to Respiratory Viruses Reveals Different Viral Strategies of Host Infection

2008 ◽  
Vol 83 (4) ◽  
pp. 1962-1968 ◽  
Author(s):  
Katherina Goris ◽  
Sabine Uhlenbruck ◽  
Christel Schwegmann-Wessels ◽  
Wiebke Köhl ◽  
Frank Niedorf ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Titer ◽  
Airway Epithelial Cells ◽  
Differential Sensitivity ◽  
Airway Epithelial ◽  
Cell Layers ◽  
Syncytial Virus ◽  
Host Infection ◽  
Precision Cut Lung Slices ◽  
Air Liquid Interface

ABSTRACT To address the initiation of virus infection in the respiratory tract, we established two culture systems for differentiated bovine airway epithelial cells (BAEC). Filter-grown BAEC differentiated under air-liquid interface (ALI) conditions to generate a pseudo-stratified mucociliary epithelium. Alternatively, precision-cut lung slices (PCLS) from the bovine airways were generated that retained the original composition and distribution of differentiated epithelial cells. With both systems, epithelial cells were readily infected by bovine parainfluenza virus 3 (BPIV3). Ciliated cells were the most prominent cell type affected by BPIV3. Surprisingly, differentiated BAEC were resistant to infection by bovine respiratory syncytial virus (BRSV), when the virus was applied at the same multiplicity of infection that was sufficient for infection by BPIV3. In the case of PCLS, infection by BRSV was observed in cells located in lower cell layers but not in epithelial cells facing the lumen of the airways. The identity of the infected cells could not be determined because of a lack of specific antibodies. Increasing the virus titer 30-fold resulted in infection of the ALI cultures of BAEC, whereas in PCLS the ciliated epithelium was still refractory to infection by BRSV. These results indicate that differentiated BAEC are readily infected by BPIV3 but rather resistant to infection by BRSV. Disease caused by BRSV may require that calves encounter environmental stimuli that render BAEC susceptible to infection.

scholarly journals Specific Inhibition of Interferon Signal Transduction Pathways by Adenoviral Infection

2001 ◽  
Vol 276 (50) ◽  
pp. 47136-47142 ◽  
Author(s):  
Theresa D. Joseph ◽  
Dwight C. Look
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Airway Epithelial Cells ◽  
Signal Transducer ◽  
Airway Epithelial ◽  
Complex Assembly ◽  
Ifn Γ

Adenoviral evolution has generated strategies to resist host cell antiviral systems, but molecular mechanisms for evasion of interferon (IFN) effects by adenoviruses during late-phase infection are poorly defined. In this study, we examined adenovirus type 5 (AdV) effects on IFN-γ-dependent gene expression and Janus family kinase-signal transducer and activator of transcription signaling components in human tracheobronchial epithelial cells. We found that AdV infection specifically inhibited IFN-γ-dependent gene expression in airway epithelial cells without evidence of epithelial cell injury or generation of a soluble extracellular inhibitor. Furthermore, infection with AdV for 18–24 h blocked phosphorylation/activation of the Stat1 transcription factor that regulates IFN-γ-dependent genes. Although AdV also inhibited IFN-α-dependent phosphorylation of Stat1 and Stat2, interleukin-4-dependent phosphorylation of the related transcription factor Stat6 was not affected, indicating that the virus selectively affected specific signaling pathways. Our results indicate that AdV inhibition of the IFN-γ signal transduction cascade occurs through loss of ligand-induced receptor complex assembly and consequent component phosphorylation and suggest that lack of complex assembly is due to decreased expression of the IFN-γR2 chain of the IFN-γ receptor. IFN-γR2 is required at an early step in Janus family kinase-signal transducer and activator of transcription pathway activation and is expressed at low levels in airway epithelial cells, supporting the concept that adenoviral down-regulation of the level of this IFN-γ receptor component allows for persistent modulation of IFN-γ-dependent gene expression.

Accessory cell function of airway epithelial cells

2004 ◽  
Vol 287 (2) ◽  
pp. L318-L331 ◽  
Author(s):  
Erwin Oei ◽  
Thomas Kalb ◽  
Prarthana Beuria ◽  
Matthieu Allez ◽  
Atsushi Nakazawa ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Cell Function ◽  
Airway Epithelial Cells ◽  
Accessory Cell ◽  
Airway Epithelial ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Oei, Erwin, Thomas Kalb, Prarthana Beuria, Matthieu Allez, Atsushi Nakazawa, Miyuki Azuma, Michael Timony, Zanetta Stuart, Houchu Chen, and Kirk Sperber. Accessory cell function of airway epithelial cells.We previously demonstrated that airway epithelial cells (AECs) have many features of accessory cells, including expression of class II molecules CD80 and CD86 and functional Fcγ receptors. We have extended these studies to show that freshly isolated AECs have mRNA for cathepsins S, V, and H [proteases important in antigen (Ag) presentation], invariant chain, human leukocyte antigen (HLA)-DM-α and HLA-DM-β, and CLIP, an invariant chain breakdown product. A physiologically relevant Ag, ragweed, was colocalized with HLA-DR in AECs, and its uptake was increased by granulocyte-macrophage colony-stimulating factor and IFN-γ treatments, which had no effect on CD80 and CD86 expression. We demonstrate the presence of other costimulatory molecules, including B7h and B7-H1, on AECs and the increased expression of B7-H1 on AECs after treatment with granulocyte-macrophage colony-stimulating factor and IFN-γ. Finally, we compared T cell proliferation after allostimulation with AECs and dendritic cells (DCs). The precursor frequency of peripheral blood T cells responding to AECs was 0.264% compared with 0.55% for DCs. DCs stimulated CD45RO+, CD45RA+, CCR7+and CCR7−CD4+, and CD8+T cells, whereas AECs stimulated only CD45RO+, CD45RA−, CCR7−, CD4+, and CD8+T cells. There was no difference in cytokine production, type of memory T cells stimulated (effector vs. long-term memory), or apoptosis by T cells cocultured with AECs and DCs. The localization of AECs exposed to the external environment may make them important in the regulation of local immune responses.

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