Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells
Aass, Kristin Roseth; Mjelle, Robin; Kastnes, Martin Haugrud; Tryggestad, Synne Stokke; van den Brink, Luca M; Roseth, Ingrid Aass; Westhrin, Marita; Zahoor, Muhammad; Moen, Siv Helen; Nedal, Tonje Marie Vikene; Buene, Glenn; Misund, Kristine; Sponaas, Anne-Marit; Ma, Qianli; Sundan, Anders; Groen, Richard WJ; Slørdahl, Tobias Schmidt; Waage, Anders; Standal, Therese
Journal article, Peer reviewed
Published version
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Date
2021Metadata
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- Institutt for klinisk og molekylær medisin [3578]
- Publikasjoner fra CRIStin - NTNU [38484]
- St. Olavs hospital [2558]
Original version
10.1016/j.isci.2021.103605Abstract
Interleukin-32 (IL-32) is a nonclassical cytokine expressed in cancers, inflammatory diseases, and infections. Its expression is regulated by two different oxygen sensing systems; HIF1α and cysteamine dioxygenase (ADO), indicating that IL-32 may be involved in the response to hypoxia. We here demonstrate that endogenously expressed, intracellular IL-32 interacts with components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in three myeloma cell lines reduced cell survival and proliferation in vitro and in vivo. High-throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that cells depleted of IL-32 had perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors, and citrate. IL-32 was expressed in a subgroup of myeloma patients with inferior survival, and primary myeloma cells expressing IL-32 had a gene signature associated with immaturity, proliferation, and oxidative phosphorylation. In conclusion, we demonstrate a previously unrecognized role of IL-32 in the regulation of plasma cell metabolism.