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

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.

• Authors: 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
• Journal: iScience (iScience) Vol. 25 Issue 1 Pg. 103605 (Jan 21 2022) ISSN: 2589-0042 [Electronic] United States
• PMID: 35005550 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).