IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells
Aass, K. R.; Mjelle, R.; Kastnes, M. H.; Tryggestad, S. S.; van den Brink, L. M.; Westhrin, M.; Zahoor, M.; Moen, S. H.; Buene, G.; Misund, K.; Sponaas, A.-M.; Ma, Q.; Sundan, A.; Groen, R. W.; Slordahl, T. S.; Waage, A.; Standal, T.
Show abstract
IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.
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