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

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) gamma and CC chemokine release by interleukin 15 (IL-15) primed human NK cells in vitro. Hypoxia inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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 IFN gamma production, but it did not affect cytotoxic granule degranulation up on target cell contact. We conclude that IL-15 priming promotes the HIF-1 alpha dependent hypoxia response and the early cytokine response in NK cells predominantly through STAT3 signaling.

Automated summary

Our study demonstrates that hypoxia and low glucose do not affect early cytokine release by IL-15 primed human NK cells in vitro. STAT3, but not mTORC1 activation, plays a key role in the HIF-1 alpha accumulation, glycolysis, and oxygen consumption under hypoxic conditions.