STAT3 governs the HIF-1α response in IL-15 primed human NK cells

• Published in: Scientific reports 2021-03, Vol.11 (1), p.7023-7023, Article 7023
• Main Authors: Coulibaly, Anna, Velásquez, Sonia Y., Kassner, Nina, Schulte, Jutta, Barbarossa, Maria Vittoria, Lindner, Holger A.
• Format: Article
• Language: English
• Subjects: 631/250; 631/45; 631/80; CCL3 protein; CCL4 protein; Cell Degranulation; Cell Hypoxia; Chemokines; Cytokines; Cytotoxicity; Degranulation; Flow Cytometry; Glycolysis; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunophenotyping; Interleukin 12; Interleukin 15; Interleukin 18; Interleukin-15 - pharmacology; K562 Cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolic flux; multidisciplinary; Natural killer cells; Oxygen consumption; Phosphorylation; Polymerase chain reaction; Rapamycin; Science; Science (multidisciplinary); Stat3 protein; STAT3 Transcription Factor - physiology; TOR protein; Transcription; Western blotting; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84916-0

Natural killer (NK) cells mediate innate host defense against microbial infection and cancer. Hypoxia and low glucose are characteristic for these tissue lesions but do not affect early interferon (IFN) γ and CC chemokine release by interleukin 15 (IL-15) primed human NK cells in vitro. Hypoxia inducible factor 1α (HIF-1α) mediates cellular adaption to hypoxia. Its production is supported by mechanistic target of rapamycin complex 1 (mTORC1) and signal transducer and activator of transcription 3 (STAT3). We used chemical inhibition to probe the importance of mTORC1 and STAT3 for the hypoxia response and of STAT3 for the cytokine response in isolated and IL-15 primed human NK cells. Cellular responses were assayed by magnetic bead array, RT-PCR, western blotting, flow cytometry, and metabolic flux analysis. STAT3 but not mTORC1 activation was essential for HIF-1α accumulation, glycolysis, and oxygen consumption. In both primed normoxic and hypoxic NK cells, STAT3 inhibition reduced the secretion of CCL3, CCL4 and CCL5, and it interfered with IL-12/IL-18 stimulated IFNγ production, but it did not affect cytotoxic granule degranulation up on target cell contact. We conclude that IL-15 priming promotes the HIF-1α dependent hypoxia response and the early cytokine response in NK cells predominantly through STAT3 signaling.