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.
Highlights
Upon inflammation, natural killer (NK) cells undergo metabolic changes to support their high energy demand for effector function and proliferation
We demonstrate that IL-18 is a potent cytokine that can enhance the expression of the nutrient transporter CD98/L-type amino acid transporter 1 (LAT1) for amino acids independently of the mTORC1 pathway and thereby induce a dramatic metabolic change associated with increased proliferation of NK cells
Because we reasoned that the metabolic demands needed for the intense NK cell proliferation can be fulfilled by high expression of nutrient transporters, the expression of amino acid transporter CD98 on proliferating NK cells in regard to cell division was analyzed
Summary
Nutrient transporters are highly expressed on proliferating NK cells upon IL-18 stimulation. Expression of Slc7a5 and Slc1a5 was up-regulated by IL-18 (Fig. 5A), indicating that all nutrient transporters necessary for the bidirectional transport of leucine/glutamine via the System L transporter are highly induced by IL-18 stimulation. NK cells stimulated with IL-2/18 in the presence of BCH showed reduced effector functions in regard to IFN-␥ production, granzyme B expression, and mTORC1 activation (Fig. 5E). These results demonstrated that IL-18 can up-regulate the expression of a wide range of amino acid transporters and induce metabolic changes in NK cells. The data demonstrated that increased expression of the System L amino acid transporter by IL-18 stimulation can intensify mTORC1 activation by leucine
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