Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression.

ABSTRACT

The interaction of multiple myeloma (MM) cells with macrophages (MΦs) contributes to the pathophysiology of MM. We previously showed that IL-32 is overexpressed in MM patients. The present study was designed to explore the clinical significance of IL-32 in MM and to further elucidate the mechanisms underlying the IL-32-mediated immune function of MΦs. Our results showed that high IL-32 expression in MM patients was associated with more advanced clinical stage. RNA-sequencing revealed that IL-32γ significantly induced the production of the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO) in MΦs, and this effect was verified by qRT-PCR, western blotting, and immunofluorescence. Furthermore, MM cells with IL-32-knockdown showed a reduced ability to promote IDO expression. As a binding protein for IL-32, proteinase 3 (PR3) was universally expressed on the surfaces of MΦs, and knockdown of PR3 or inhibition of the STAT3 and NF-κB pathways hindered the IL-32γ-mediated stimulation of IDO expression. Finally, IDO-positive IL-32γ-educated MΦs inhibited CD4+ T cell proliferation and IL-2, IFN-γ, and TNF-α production. Taken together, our results indicate that IL-32γ derived from MM cells promotes the immunosuppressive function of MΦs and is a potential target for MM treatment.