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

Abstract 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. Hyp...

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Autores principales:	Anna Coulibaly, Sonia Y. Velásquez, Nina Kassner, Jutta Schulte, Maria Vittoria Barbarossa, Holger A. Lindner
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/241d538460a74c8eb2e876ba1dfab688
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spelling	oai:doaj.org-article:241d538460a74c8eb2e876ba1dfab6882021-12-02T14:25:03ZSTAT3 governs the HIF-1α response in IL-15 primed human NK cells10.1038/s41598-021-84916-02045-2322https://doaj.org/article/241d538460a74c8eb2e876ba1dfab6882021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84916-0https://doaj.org/toc/2045-2322Abstract 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.Anna CoulibalySonia Y. VelásquezNina KassnerJutta SchulteMaria Vittoria BarbarossaHolger A. LindnerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Coulibaly Sonia Y. Velásquez Nina Kassner Jutta Schulte Maria Vittoria Barbarossa Holger A. Lindner STAT3 governs the HIF-1α response in IL-15 primed human NK cells
description	Abstract 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.
format	article
author	Anna Coulibaly Sonia Y. Velásquez Nina Kassner Jutta Schulte Maria Vittoria Barbarossa Holger A. Lindner
author_facet	Anna Coulibaly Sonia Y. Velásquez Nina Kassner Jutta Schulte Maria Vittoria Barbarossa Holger A. Lindner
author_sort	Anna Coulibaly
title	STAT3 governs the HIF-1α response in IL-15 primed human NK cells
title_short	STAT3 governs the HIF-1α response in IL-15 primed human NK cells
title_full	STAT3 governs the HIF-1α response in IL-15 primed human NK cells
title_fullStr	STAT3 governs the HIF-1α response in IL-15 primed human NK cells
title_full_unstemmed	STAT3 governs the HIF-1α response in IL-15 primed human NK cells
title_sort	stat3 governs the hif-1α response in il-15 primed human nk cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/241d538460a74c8eb2e876ba1dfab688
work_keys_str_mv	AT annacoulibaly stat3governsthehif1aresponseinil15primedhumannkcells AT soniayvelasquez stat3governsthehif1aresponseinil15primedhumannkcells AT ninakassner stat3governsthehif1aresponseinil15primedhumannkcells AT juttaschulte stat3governsthehif1aresponseinil15primedhumannkcells AT mariavittoriabarbarossa stat3governsthehif1aresponseinil15primedhumannkcells AT holgeralindner stat3governsthehif1aresponseinil15primedhumannkcells
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STAT3 governs the HIF-1α response in IL-15 primed human NK cells

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