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J Biol Chem. 2019 Mar 22;294(12):4644-4655. doi: 10.1074/jbc.RA118.005892. Epub 2019 Jan 29.

Interleukin-18 up-regulates amino acid transporters and facilitates amino acid-induced mTORC1 activation in natural killer cells.

Author information

1
From the Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and.
2
Botany and Microbiology Department, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
3
From the Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and seunglee@uottawa.ca.

Abstract

Upon inflammation, natural killer (NK) cells undergo metabolic changes to support their high energy demand for effector function and proliferation. The metabolic changes are usually accompanied by an increase in the expression of nutrient transporters, leading to increased nutrient uptake. Among various cytokines inducing NK cell proliferation, the mechanisms underlying the effect of interleukin (IL)-18 in promoting NK cell proliferation are not completely understood. Here, we demonstrate that IL-18 is a potent cytokine that can enhance the expression of the nutrient transporter CD98/LAT1 for amino acids independently of the mTORC1 pathway and thereby induce a dramatic metabolic change associated with increased proliferation of NK cells. Notably, treatment of IL-18-stimulated NK cells with leucine activates the metabolic sensor mTORC1, indicating that the high expression of amino acid transporters induces amino acid-driven mTORC1 activation. Inhibition of the amino acid transporter CD98/LAT1 abrogated the leucine-driven mTORC1 activation and reduced NK cell effector function. Taken together, our study identified a novel role of IL-18 in up-regulating nutrient transporters on NK cells and thereby inducing metabolic changes, including the mTORC1 activation by amino acids.

KEYWORDS:

amino acid; cell metabolism; cell proliferation; interleukin-18 (IL-18); mTORC1; mammalian target of rapamycin (mTOR); natural killer cells (NK cells); nutrient uptake

PMID:
30696773
PMCID:
PMC6433059
[Available on 2020-03-22]
DOI:
10.1074/jbc.RA118.005892

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