Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells

Kristin Roseth Aass; Robin Mjelle; Martin H Kastnes; Synne S Tryggestad; Luca M van den Brink; Ingrid Aass Roseth; Marita Westhrin; Muhammad Zahoor; Siv H Moen; Tonje M Vikene Nedal; Glenn Buene; Kristine Misund; Anne-Marit Sponaas; Qianli Ma; Anders Sundan; Richard Wj Groen; Tobias S Slørdahl; Anders Waage; Therese Standal

doi:10.1016/j.isci.2021.103605

Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells

iScience. 2021 Dec 13;25(1):103605. doi: 10.1016/j.isci.2021.103605. eCollection 2022 Jan 21.

Authors

Kristin Roseth Aass^{1

2}, Robin Mjelle², Martin H Kastnes^{1

2}, Synne S Tryggestad^{1

2}, Luca M van den Brink¹, Ingrid Aass Roseth^{1

2}, Marita Westhrin¹, Muhammad Zahoor³, Siv H Moen^{1

2}, Tonje M Vikene Nedal^{1

2}, Glenn Buene^{1

2}, Kristine Misund², Anne-Marit Sponaas², Qianli Ma^{1

2}, Anders Sundan^{1

2}, Richard Wj Groen⁴, Tobias S Slørdahl^{2

5}, Anders Waage^{2

5}, Therese Standal^{1

2

5}

Affiliations

¹ Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway.
² Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
³ Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo 0372, Norway.
⁴ Department of Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam 1081, the Netherlands.
⁵ Department of Hematology, St.Olavs University Hospital, Trondheim 7491, Norway.

Abstract

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.

Keywords: Cancer; Cell biology; Immunology.