Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2, 3-dioxygenase (IDO) expression. (1st April 2019)

• Record Type: Journal Article
• Authors: Yan, Haimeng; Dong, Mengmeng; Liu, Xinling; Shen, Qiang; He, Donghua; Huang, Xi; Zhang, Enfan; Lin, Xuanru; Chen, Qingxiao; Guo, Xing; Chen, Jing; Zheng, Gaofeng; Wang, Gang; He, Jingsong; Yi, Qing; Cai, Zhen
• Is Part Of: Cancer letters. Volume 446(2019)
• Page Start: 38
• Page End: 48
• Publication Date: 2019-04-01
• Subjects: Interleukin-32 -- Malignant plasma cell -- IDO -- Microenvironment -- MΦs; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.01.012
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: IL-32 was universally expressed in BM biopsies from MM patients. IL-32 expression was positively correlated with MM clinical stage. IL-32γ in MM cells induced IDO production in MΦs through PR3. IDO-positive IL-32γ-educated MΦs inhibited proliferation and effector function of CD4 + T cells. IL-32γ-induced IDO expression depended on STAT3 and NF-κB pathways.