scholarly journals HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3343-3354 ◽  
Author(s):  
Marzia Scortegagna ◽  
Christophe Cataisson ◽  
Rebecca J. Martin ◽  
Daniel J. Hicklin ◽  
Robert D. Schreiber ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cancer Metastasis ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Local Environment ◽  
Inflammatory Cells ◽  
Hypoxia Inducible Factor 1 ◽  
Inflammatory Protein ◽  
Multiple Cell ◽  
Epithelial Inflammation

AbstractHypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.

scholarly journals The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro and in vivo by targeting the hypoxia inducible factor-1 pathway

2014 ◽  
Vol 13 (1) ◽  
pp. 12 ◽  
Author(s):  
Khaled Ghattass ◽  
Sally El-Sitt ◽  
Kazem Zibara ◽  
Saide Rayes ◽  
Makhluf J Haddadin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Hypoxia Inducible Factor ◽  
Breast Cancer Metastasis ◽  
Hypoxia Inducible Factor 1

scholarly journals Adhatoda Vasica: A Potential Ayurvedic Intervention Against COVID-19 Associated Impaired Immune Response and Hypoxia-Inflammation Phenotype

2020 ◽  
Author(s):  
Atish Prabhakar Gheware ◽  
Dhwani Dholakia ◽  
S Kanan ◽  
Lipsa Panda ◽  
Vivek Anand ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Viral Entry ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Adhatoda Vasica ◽  
Hypoxia Inducible Factor 1 ◽  
Infection And Inflammation ◽  
Impaired Immune Response ◽  
Host Target

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. Methods: In this study we tested the effect of whole aqueous extract Adhatoda Vasica (AV), that our group has shown to have anti-hypoxic and anti-inflammatory effects, on various outcomes of hypoxic response. Effects of AV were assessed in preclinical mouse models of pulmonary fibrosis, bacterial sepsis and siRNA induced hypoxia-thrombosis phenotype. Therapeutic relevance of AV in current pandemic were also examined through transcriptome and molecular docking analysis. Results: Oral administration AV extract attenuated the increased levels of airway inflammation, collagen content, transforming growth factor-b1 (TGF-b1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated and Cecum Ligation and Puncture (CLP) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, TGF-b1 and angiogenesis and upregulation of adaptive immunity related genes. These genes and pathways show opposite expression in transcriptome of BALF and PBMCs of SARS-CoV2 infected patient. Molecular docking of AV constituents presents in extract reveal many molecules with low binding energy (≤ -8) to multiple SARS-CoV2 and host target proteins that are relevant in viral entry and replication. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features which could be useful against SARS-CoV-2 infection.

scholarly journals Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts

2000 ◽  
Vol 350 (1) ◽  
pp. 307-312 ◽  
Author(s):  
Ruth D. THORNTON ◽  
Pamela LANE ◽  
Ruth C. BORGHAEI ◽  
Elizabeth A. PEASE ◽  
Jaime CARO ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Consensus Sequence ◽  
Hypoxia Inducible Factor ◽  
Synovial Fibroblasts ◽  
Consensus Binding Site ◽  
Hypoxia Inducible Factor 1 ◽  
Aryl Hydrocarbon ◽  
Factor Α ◽  
Endothelial Growth Factor

Rheumatoid arthritis and periodontitis are inflammatory diseases modulated by proinflammatory cytokines [e.g. interleukin (IL-1) 1 and tumour necrosis factor α], which activate local fibroblasts to do the following: (1) proliferate, (2) induce gene expression and (3) produce destructive metalloproteinases. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor (composed of HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear transporter) that is modulated by hypoxia. HIF-1 binds to and induces several genes containing an HIF-1 consensus-binding site, including vascular endothelial growth factor and several glycolytic enzymes. Through differential screening of a human synovial fibroblast cDNA library, we identified HIF-1α as a clone up-regulated by IL-1. The mRNA for HIF-1α subunit was increased 3–4-fold by Northern blot analysis after cells had been incubated for 3h in the presence of IL-1. In addition, IL-1 increased the binding of the heterodimer HIF-1 to the HIF consensus sequence. These results suggest that HIF-1 might have a role in inflammation, possibly in attempting to re-establish homoeostasis.

Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Patients With Cancer ◽  
Hypoxia Inducible Factor 1 ◽  
Chemically Induced ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

Sign in / Sign up

Export Citation Format

Share Document