Chemokine expression in CF epithelia: implications for the role of CFTR in RANTES expression

1999 ◽  
Vol 276 (3) ◽  
pp. C700-C710 ◽  
Author(s):  
Lisa M. Schwiebert ◽  
Kim Estell ◽  
Stacie M. Propst
Keyword(s):  
Epithelial Cells ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Rantes Promoter ◽  
Cf Transmembrane Conductance Regulator

To delineate the mechanisms that facilitate leukocyte migration into the cystic fibrosis (CF) lung, expression of chemokines, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES, was compared between CF and non-CF airway epithelia. The findings presented herein demonstrate that, under either basal conditions or tumor necrosis factor-α (TNF-α)- and/or interferon-γ (IFN-γ)-stimulated conditions, a consistent pattern of differences in the secretion of IL-8 and MCP-1 between CF and non-CF epithelial cells was not observed. In contrast, CF epithelial cells expressed no detectable RANTES protein or mRNA under basal conditions or when stimulated with TNF-α and/or IFN-γ ( P ≤ 0.05), unlike their non-CF counterparts. Correction of the CF transmembrane conductance regulator (CFTR) defect in CF airway epithelial cells restored the induction of RANTES protein and mRNA by TNF-α in combination with IFN-γ ( P ≤ 0.05) but had little effect on IL-8 or MCP-1 production compared with mock controls. Transfection studies utilizing RANTES promoter constructs suggested that CFTR activates the RANTES promoter via a nuclear factor-κB-mediated pathway. Together, these results suggest that 1) RANTES expression is altered in CF epithelia and 2) epithelial expression of RANTES, but not IL-8 or MCP-1, is dependent on CFTR.

scholarly journals Tumour necrosis factor-α and interferon-γ synergistically activate the RANTES promoter through nuclear factor κB and interferon regulatory factor 1 (IRF-1) transcription factors

2000 ◽  
Vol 350 (1) ◽  
pp. 131-138 ◽  
Author(s):  
Ahn Hwee LEE ◽  
Jeong-Ho HONG ◽  
Yeon-Soo SEO
Keyword(s):  
Binding Sites ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Regulatory Factor ◽  
Cis Acting ◽  
Tnf Α ◽  
Ifn Γ ◽  
Rantes Promoter ◽  
Factor Α ◽  
Necrosis Factor

Inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) synergistically activate expression of the RANTES (regulated upon activation, normal T-cell expressed and secreted) gene, which plays a crucial role in the chemoattraction of leukocytes during the inflammatory response. To understand at the molecular level the mechanism by which the two cytokines activate RANTES gene expression, we determined the requirement of cis-acting elements in the RANTES promoter and trans-acting factors. The murine RANTES promoter contained one putative interferon regulatory factor, IRF, and three putative nuclear factor κB (NF-κB) binding sites. Specific destruction of the IRF binding site and one of the three NF-κB binding sites abolished the inducibility of promoter activity by IFN-γ and TNF-α, respectively. In contrast, mutation of the other two putative NF-κB binding sites did not affect RANTES promoter activity significantly. In addition, the RANTES promoter was stimulated by co-transfection of plasmids that expressed either p65, an NF-κB family protein, or the IRF-1 transcription factor. RANTES promoters with mutations in the NF-κB or IRF binding sites were not stimulated by p65 or IRF-1 expression, respectively. In electrophoretic mobility-shift and immunologic assays, we showed that IRF-1 was induced after cells were treated with IFN-γ and that NF-κB was activated by TNF-α treatment. These results demonstrate that both NF-κB and IRF-1 transcription factors mediate the induction of RANTES expression via their cognate cis-acting elements when cells are stimulated by TNF-α and IFN-γ.

Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation

2002 ◽  
Vol 283 (6) ◽  
pp. L1280-L1290 ◽  
Author(s):  
Antonella Casola ◽  
Allyne Henderson ◽  
Tianshuang Liu ◽  
Roberto P. Garofalo ◽  
Allan R. Brasier
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Viral Infection ◽  
Molecular Mechanisms ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mrna Stabilization ◽  
Tnf Α ◽  
Ifn Γ ◽  
Responsive Element

Regulated on activation, normal T cell expressed, and presumably secreted (RANTES) is a member of the CC chemokine family of proteins implicated in a variety of diseases characterized by lung eosinophilia and inflammation, strongly produced by stimulated airway epithelial cells. Because such cytokines as tumor necrosis factor (TNF)-α and interferon-γ (IFN-γ) have been shown to enhance RANTES induction in airway epithelial cells and RANTES gene expression appears to be differentially regulated depending on the cell type and the stimulus applied, in this study we have elucidated mechanisms that operate to control RANTES induction on exposure to TNF-α and/or IFN-γ. Our results indicate that TNF-α and IFN-γ synergistically induce RANTES protein secretion and mRNA expression. RANTES transcription is activated only after stimulation with TNF-α, but not IFN-γ, which affects RANTES mRNA stabilization. Promoter deletion and mutagenesis experiments indicate that the nuclear factor (NF)-κB site is the most important cis-regulatory element controlling TNF-induced RANTES transcription, although NF-interleukin-6 binding site, cAMP responsive element (CRE), and interferon-stimulated responsive element (ISRE) also play a significant role. TNF-α stimulation induces nuclear translocation of interferon regulatory factor (IRF)-3, which in viral infection binds the RANTES ISRE and is necessary for activation of RANTES transcription. However, TNF-induced IRF-3 translocation does not result in IRF-3 binding to the RANTES ISRE. Although viral infection can activate an ISRE-driven promoter, TNF cannot, indicating that RANTES gene enhancers are controlled in a stimulus-specific fashion. Identification of molecular mechanisms involved in RANTES gene expression is fundamental for developing strategies to modulate lung inflammatory responses.

scholarly journals Ozone effect on inflammatory and proteomic profile of human macrophages and airway epithelial cells

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
L Falcone ◽  
E Aruffo ◽  
P Di Carlo ◽  
P Del Boccio ◽  
M C Cufaro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Air Pollution ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Urban Areas ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Proteomics Analysis ◽  
Human Macrophages ◽  
Tnf Α

Abstract Background Reactive oxygen species (ROS) and oxidative stress in the respiratory system are involved in lung inflammation and tumorigenesis. Ozone (O3) is one of the main components of air pollution in urban areas able to act as strong pro-oxidant agent, however its effects on human health is still poorly investigated. In this study the effect of O3 has been evaluated in THP-1 monocytes differentiated into macrophages with PMA and in HBEpC (primary human bronchial epithelial) cells, two model systems for in vitro studies and translational research. Methods Cell viability, ROS and pro-inflammatory cytokines like interleukin-8(IL-8) and tumor necrosis factor(TNF-α) have been tested in the above-mentioned cell lines not exposed to any kind of pollution (basal condition-b.c.) or exposed to O3 at a concentration of 120 ppb. In HBEpC a labelfree shotgun proteomics analysis has been also performed in the same conditions. Results Ozone significantly increased the production of IL-8 and TNF-α in THP-1 whereas no changes were shown in HBEpC. In both cell lines lipopolysaccharide(LPS) caused an increase of IL-8 and TNF-α production in b.c. and O3 treatment potentiated this effect. Ozone exposure increased ROS formation in a time dependent manner in both cell lines and in THP-1 cells a decrease in catalase activity was also shown. Finally, according to these data, functional proteomics analysis revealed that in HBEpC exposure to O3 many differential proteins are related to oxidative stress and inflammation. Conclusions Our results indicate that O3, at levels that can be reached in urban areas, causes an increase of pro-inflammatory agents either per se or potentiating the effect of immune response stimulators in cell models of human macrophages and human airway epithelial cells. Interestingly, the proteomic analysis showed that besides the dysregulated proteins, O3 induced the expression of AKR1D1 and AKR1B10, proteins recognized to play a significant role in cancer development. Key messages This study adds new pieces of information on the association between O3 exposure and detrimental effects on respiratory system. This study suggests the need for further research on the mechanisms involved and for a continued monitoring/re-evaluation of air pollution standards aimed at safeguarding human health.

Clinical significance of cytokine markers in children with different courses of community-acquired pneumonia

2020 ◽  
Vol 15 (5) ◽  
pp. 18-23
Author(s):  
G.P. Evseeva ◽  
◽  
G.N. Kholodok ◽  
S.V. Pichugina ◽  
S.V. Suprun ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Interleukin 1 ◽  
Interferon Γ ◽  
Peripheral Blood Lymphocytes ◽  
Community Acquired Pneumonia ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 17 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Ifn Γ

Principles of the diagnosis and treatment of community-acquired pneumonia (CAP) in children were developed and clearly formulated long ago. Nevertheless, clinicians often encounter the problem of pulmonary and pleural complications of CAP, which is challenging in terms of the choice of initial therapy, since the first symptoms of uncomplicated and complicated pneumonia are often similar. Therefore, the search for early markers of complicated CAP in children is highly important. Objective. To assess prognostic values of spontaneous and mitogen-induced cytokine production in children with CAP. Patients and methods. We have performed comprehensive examination of 108 children with CAP. Eighty-four of them had uncomplicated CAP, whereas 24 children had CAP complicated by pleurisy. We measured spontaneous and induced production of the following cytokines upon patient admission to hospital: interleukin-1 (IL-1), interleukin-17 (IL-17), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). To measure induced cytokine production, we stimulated peripheral blood lymphocytes by S. рneumonае (serotype 7, 11; strains 7C and 11AD). The level of cytokines was evaluated using the enzyme-linked immunosorbent assay (Vektor-BEST, Novosibirsk, Russia). Results. We found that in children with uncomplicated CAP, induction of immunocompetent blood cells (IBCs) led to increased secretion of first-generation cytokines, including IL-1, TNF-α, and IFN-γ, whereas IBCs of patients with complicated CAP primarily produced second-generation cytokines, including VEGF, МРС-1, and IL-17. Conclusion. The observed differences in spontaneous and mitogen-induced cytokine production between children with and without CAP complications suggest that these parameters can be considered as promising prognostic markers for complicated CAP in children. The proposed method can be used in pediatric practice to predict the development of complications in children with CAP. Key words: children, community-acquired pneumonia, cytokines

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.

scholarly journals Interferon-γ Inhibits STAT6 Signal Transduction and Gene Expression in Human Airway Epithelial Cells

2004 ◽  
Vol 31 (5) ◽  
pp. 573-582 ◽  
Author(s):  
Nicola M. Heller ◽  
Satoshi Matsukura ◽  
Steve N. Georas ◽  
Mark R. Boothby ◽  
Paul B. Rothman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Epithelial Cells ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Human Airway ◽  
Human Airway Epithelial Cells

Inhibition of TNF-α-Induced MUC5AC Mucin Gene Expression and Production by Wogonin Through the Inactivation of NF-κB Signaling in Airway Epithelial Cells

2013 ◽  
Vol 28 (1) ◽  
pp. 62-68 ◽  
Author(s):  
Md. Asaduzzaman Sikder ◽  
Hyun Jae Lee ◽  
Md. Zakaria Mia ◽  
Su Hyun Park ◽  
Jiho Ryu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mucin Gene ◽  
Tnf Α

scholarly journals The expression of the eotaxins IL-6 and CXCL8 in human epithelial cells from various levels of the respiratory tract

2013 ◽  
Vol 18 (4) ◽  
Author(s):  
Magdalena Paplińska-Goryca ◽  
Patrycja Nejman-Gryz ◽  
Ryszarda Chazan ◽  
Hanna Grubek-Jaworska
Keyword(s):  
Epithelial Cells ◽  
Respiratory Tract ◽  
Airway Epithelial Cells ◽  
Small Airway ◽  
Primary Cells ◽  
Human Epithelial Cells ◽  
Tnf Α ◽  
Normal Human ◽  
Ifn Γ ◽  
Pre Treatment

AbstractAirway epithelium acts as multifunctional site of response in the respiratory tract. Epithelial activity plays an important part in the pathophysiology of obstructive lung disease. In this study, we compare normal human epithelial cells from various levels of the respiratory tract in terms of their reactivity to pro-allergic and pro-inflammatory stimulation. Normal human nasal, bronchial and small airway epithelial cells were stimulated with IL-4 and IL-13. The expressions of the eotaxins IL-6 and CXCL8 were evaluated at the mRNA and protein levels. The effects of pre-treatment with IFN-γ on the cell reactivity were measured, and the responses to TNF-α, LPS and IFN-γ were evaluated. All of the studied primary cells expressed CCL26, IL-6 and IL-8 after IL-4 or IL-13 stimulation. IFN-γ pre-treatment resulted in decreased CCL26 and increased IL-6 expression in the nasal and small airway cells, but this effect was not observed in the bronchial cells. IL-6 and CXCL8 were produced in varying degrees by all of the epithelial primary cells in cultures stimulated with TNF-α, LPS or IFN-γ. We showed that epithelial cells from the various levels of the respiratory tract act in a united way, responding in a similar manner to stimulation with IL-4 and IL-13, showing similar reactivity to TNF-α and LPS, and giving an almost unified response to IFN-γ pre-stimulation.

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