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Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells.

ABSTRACT: BACKGROUND:Interferon gamma (IFN?) plays an important role in the development of chronic lung diseases via the production of inflammatory mediators, although the exact mechanism remains unclear. The present study aimed at investigating the potential mechanisms by which IFN? induced over-production of interleukins through the interaction between carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway. METHODS:IFN-? induced over-production of interleukin (IL) 6 and IL8, and RNA expression of CEACAM1 and its subtypes or PI3K and its subtypes in human bronchial epithelial cells (HBE). The production of IL6 and IL8 or cell proliferation and movement were also evaluated in cellCEACAM1- or cellCEACAM1+ after the induction of IFN-?. Roles of PI3K subtype proteins, e.g. PI3Kp110?/?, Akt, p110?/?/?/?/mTOR, PI3Kp110?/?/?, PI3Kp110?, or pan-PI3K in IFN-?-induced CEACAM1 subtype alterations were furthermore validated using those proteins of PI3K subtypes. RESULTS:CEACAM1, especially CEACAM1-S isoforms, was significantly up-regulated in HBE cells after treatment with IFN-?. CEACAM1 played roles in expression of IL-6 and IL-8, and facilitated cellular proliferation and migration. IFN-? up-regulated the expression of CEACAM1 in airway epithelial cells, especially CEACAM1-S isoforms, promoting cellular proliferation, migration, and the production of inflammatory factors. PI3K (p110?)/Akt/mTOR pathway was involved in the process of IFN-?-upregulated CEACAM1, especially CEACAM1-S. On the other hand, CEACAM1 could promote the activation of PI3K/Akt/mTOR pathway. CONCLUSION:IFN-? could induce inflammatory responses, cellular growth and proliferation through the interaction of CEACAM1 (especially CEACAM1-S isoforms) and PI3K(p110?)/Akt/mTOR in airway epithelial cells, which might be new alternative of future therapies against epithelial transition from inflammation to cancer.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC6507156 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells.

Zhu Yichun Y Song Dongli D Song Yuanlin Y Wang Xiangdong X

Journal of translational medicine 20190509 1

<h4>Background</h4>Interferon gamma (IFNγ) plays an important role in the development of chronic lung diseases via the production of inflammatory mediators, although the exact mechanism remains unclear. The present study aimed at investigating the potential mechanisms by which IFNγ induced over-production of interleukins through the interaction between carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway.<h4>Methods ...[more]

PMID: 31072323

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Project description:Human rhinoviruses (HRV) cause the majority of colds and trigger exacerbations of chronic lower airway diseases. Airway epithelial cells are the primary site for HRV infection and replication, and the initiation of host inflammatory responses. At present, the molecular mechanisms that underpin HRV responses in airway epithelial cells are incompletely understood. The aim of this study was to employ microarray profiling, upstream regulator analysis, and siRNA mediated gene silencing to further our understanding of the role of interferon regulatory factor 7 (IRF7) in this response.Primary human bronchial epithelial cells (HBE) where transfected with siRNA that targets IRF7 or a non-silencing control (all-star control) using Lipofectamine. The cells were allowed to recover, and then cultured in the presence or absence of HRV-16 for 24 h. Global patterns of gene expression were profiled on microarrays. A subset of genes identified in the microarray study were validated at the mRNA and/or protein level using real time RT-qPCR, ELISA, and western blots.Hundreds of genes were upregulated in HBE during HRV infection. Pathways analysis demonstrated that these genes were mainly involved in type I and II interferon signaling, RIG-I/MDA5 signaling, antigen processing and presentation, and apoptosis. Upstream regulator analysis of these data suggested that IRF7 was a major molecular driver of this response. Knockdown of IRF7 reduced the HRV-driven upregulation of genes involved in antiviral responses (interferon signaling, Toll-like receptor signaling, NOD-like receptor signaling, RIG-I/MDA5 signaling), and increased the expression of genes that promote inflammation (e.g. CXCL5, IL-33, IL1RL1) and the response to oxidative stress. However, the majority of genes that were perturbed by HRV in HBE cells including those that are known to be regulated by IRF7 were insensitive to IRF7 knockdown. Upstream regulator analysis of the part of the response that was insensitive to IRF7 knockdown suggested it was driven by NF-?B, STAT1, STAT3, and IRF1.Our findings demonstrate that IRF7 regulates the expression of genes involved in antiviral immunity, inflammation, and the response to oxidative stress during HRV infections in HBE cells, and also suggests that other transcription factors play a major role in this response.

Project description:BackgroundTumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development.MethodsIFN was used to induce inflammation response and HIF-1? expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1? in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation.ResultsWe showed for the first time that IFN induced functional HIF-1? expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1? pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1?, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1? is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1?-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay.ConclusionsOur mechanistic study showed an induction of HIF-1? and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1? may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1? programming.

Dataset Information

Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells.

Publications

Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells.

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