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

iScience (Jan 2022)

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

Affiliations

Kristin Roseth Aass: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Robin Mjelle: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Martin H. Kastnes: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Synne S. Tryggestad: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Luca M. van den Brink: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway
Ingrid Aass Roseth: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Marita Westhrin: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway
Muhammad Zahoor: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo 0372, Norway
Siv H. Moen: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Tonje M. Vikene Nedal: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Glenn Buene: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Kristine Misund: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Anne-Marit Sponaas: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Qianli Ma: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Anders Sundan: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Richard WJ. Groen: Department of Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam 1081, the Netherlands
Tobias S. Slørdahl: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Hematology, St.Olavs University Hospital, Trondheim 7491, Norway
Anders Waage: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Hematology, St.Olavs University Hospital, Trondheim 7491, Norway
Therese Standal: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Hematology, St.Olavs University Hospital, Trondheim 7491, Norway; Corresponding author

Journal volume & issue: Vol. 25, no. 1
p. 103605

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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