ArticleThe Journal of biological chemistry2016
Short Term Hypoxia Synergizes with Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 80 citations in OpenAlex.
- Metabolic licensing at the dendritic cell-NK cells immune synapse in viral asthma exacerbations.Frontiers in immunology · 2026Review
- CAR-NK Engineering to Overcome TME Barriers.Cells · 2025Review
- Mendelian randomization study explores the peripheral immunological characteristics of colorectal cancer.Discover oncology · 2025Article
- Hypoxia and IL-15 Cooperate to Induce Perforin Expression by CD8 T Cells and Promote Damage to the Skin in Murine Cutaneous Leishmaniasis.The Journal of investigative dermatology · 2025Article
- Tumor hypoxia shapes natural killer cell anticancer activities.Journal of molecular medicine (Berlin, Germany) · 2025Review
- Tumor-Associated Extracellular Matrix Obstacles for CAR-T Cell Therapy: Approaches to Overcoming.Current oncology (Toronto, Ont.) · 2025Review
- Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments.Science advances · 2024Article
- Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.Frontiers in immunology · 2024Review
- Mechanisms of HIF-driven immunosuppression in tumour microenvironment.Journal of the Egyptian National Cancer Institute · 2023Review
- Addressing Natural Killer Cell Dysfunction and Plasticity in Cell-Based Cancer Therapeutics.Cancers · 2023Review
- The effect of curcumin on hypoxia in the tumour microenvironment as a regulatory factor in cancer.Archives of medical science : AMS · 2023Article
- Immunologic and vascular biomarkers of mortality in critical COVID-19 in a South African cohort.Frontiers in immunology · 2023Article
- Chimeric antigen receptor-engineered NK cells: new weapons of cancer immunotherapy with great potential.Experimental hematology & oncology · 2022Review
- Hypoxia-inducible factor-1 alpha expression is induced by IL-2 via the PI3K/mTOR pathway in hypoxic NK cells and supports effector functions in NKL cells and ex vivo expanded NK cells.Cancer immunology, immunotherapy : CII · 2022Article
- TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment.Journal of translational medicine · 2022Review
- Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy.Cancers · 2022Review
- iPSCs in NK Cell Manufacturing and NKEV Development.Frontiers in immunology · 2022Review
- The Dynamic Role of NK Cells in Liver Cancers: Role in HCC and HBV Associated HCC and Its Therapeutic Implications.Frontiers in immunology · 2022Review
- The Metabolic Basis of ILC Plasticity.Frontiers in immunology · 2022Review
- Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Natural killer (NK) cells induce apoptosis in infected and transformed cells and are important producers of immunoregulatory cytokines. Therefore, they operate under low oxygen conditions (hypoxia) in inflammatory and tumor environments. In vitro studies of NK cells are, however, commonly performed in ambient air (normoxia). We used global gene expression profiling to evaluate changes in transcriptional pathways in primary human NK cells following short term culture under hypoxia compared with normoxia and in response to interleukin 15 (IL-15) priming using a 2 × 2 factorial design. The largest contrasts observed were priming dependences for associations between hypoxia and the hypoxia-inducible factor (Hif) 1 signaling and glycolysis pathways. RT-PCR confirmed positive synergistic hypoxia/IL-15 interactions for genes of key regulatory and metabolic enzymes. IL-15 primes NK cells for effector functions, which were recently demonstrated to depend on glycolytic switching. We did not, however, observe important increases in glycolytic flux through hypoxia and priming alone. Chemical Hif-1α inhibition suggested equal importance of this transcription factor for glycolysis and energy production under normoxia and hypoxia. Hypoxia promoted secretion of CC chemokines Ccl3/4/5 and macrophage migration inhibitory factor. Unexpectedly, hypoxia also stimulated migration of NK cells through the extracellular matrix and shifted amounts of susceptible leukemia target cells toward late apoptosis in a cell killing assay. We conclude that short term hypoxia supports these activities by positively interacting with NK cell priming at the level of glycolytic gene transcription. Hypoxic conditioning of NK cells may thus benefit their use in cell-based immunotherapy of cancer.
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