TY - JOUR
T1 - Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells
AU - Roseth Aass, Kristin
AU - Mjelle, Robin
AU - Kastnes, Martin H.
AU - Tryggestad, Synne S.
AU - van den Brink, Luca M.
AU - Aass Roseth, Ingrid
AU - Westhrin, Marita
AU - Zahoor, Muhammad
AU - Moen, Siv H.
AU - Vikene Nedal, Tonje M.
AU - Buene, Glenn
AU - Misund, Kristine
AU - Sponaas, Anne-Marit
AU - Ma, Qianli
AU - Sundan, Anders
AU - Groen, Richard W. J.
AU - Slørdahl, Tobias S.
AU - Waage, Anders
AU - Standal, Therese
N1 - Funding Information:
The authors thank Berit Størdal and Hanne Hella for technical support and Pegah Abdollahi for help and training in experimental procedures. The confocal imaging services were provided by the Cellular and Molecular Imaging Core Facility (CMIC), Norwegian University of Science and Technology (NTNU), which is funded by the Faculty of Medicine at NTNU and Central Norway Regional Health Authority . We thank previous and current members of our patient advisory board and the Multiple Myeloma Research Foundation Personalized Medicine Initiatives ( https://research.themmrf.org and www.themmrf.org ), which generated the CoMMpass data. This work was supported by funds from the Norwegian Cancer Society ( #206643 , #191861 ), the Research Council of Norway ( #223255 ), the Liaison Committee for education, research and innovation in Central Norway (# 90061000 and # 30171600 ), and the Cancer Fund at St. Olavs Hospital , Trondheim, Norway.
Publisher Copyright:
© 2021 The Author(s)
PY - 2022/1/21
Y1 - 2022/1/21
N2 - 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.
AB - 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.
KW - Cancer
KW - Cell biology
KW - Immunology
UR - http://www.scopus.com/inward/record.url?scp=85121641102&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103605
DO - 10.1016/j.isci.2021.103605
M3 - Article
C2 - 35005550
VL - 25
JO - iScience
JF - iScience
SN - 2589-0042
IS - 1
M1 - 103605
ER -