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

Haimeng Yan, Mengmeng Dong, Xinling Liu, Qiang Shen, Donghua He, Xi Huang, Enfan Zhang, Xuanru Lin, Qingxiao Chen, Xing Guo, Jing Chen, Gaofeng Zheng, Gang Wang, Jingsong He, Qing Yi, Zhen Cai

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)38-48
Number of pages11
JournalCancer Letters
Volume446
DOIs
StatePublished - Apr 1 2019

Keywords

  • IDO
  • Interleukin-32
  • Malignant plasma cell
  • Microenvironment
  • MΦs

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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