Multiple myeloma cell-derived IL-32gamma increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression.
Multiple myeloma cell-derived IL-32gamma increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression.
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多发性骨髓瘤细胞来源的 IL-32gamma 通过促进吲哚胺 2,3-双加氧酶 (IDO) 表达来增强巨噬细胞的免疫抑制功能。
DOI：
10.1016/j.canlet.2019.01.012
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发表时间：
2019
期刊：
影响因子：
9.7
通讯作者：
Cai Zhen
中科院分区：
文献类型：
--
作者：
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
多发性骨髓瘤（MM）细胞与巨噬细胞（MΦs）的相互作用有助于MM的病理生理。我们之前发现IL-32在MM患者中过表达。本研究旨在探讨IL-32在MM中的临床意义，并进一步阐明IL-32介导MΦs免疫功能的机制。我们的研究结果表明，IL-32在MM患者中的高表达与更晚期的临床阶段相关。rna测序结果显示，IL-32γ显著诱导MΦs中免疫抑制分子吲哚胺2,3-双加氧酶（IDO）的产生，并通过qRT-PCR、western blotting和免疫荧光验证了这一作用。此外，il -32敲低的MM细胞促进IDO表达的能力降低。蛋白酶3 （PR3）是IL-32的结合蛋白，在MΦs表面普遍表达，敲低PR3或抑制STAT3和NF-κB通路会阻碍IL-32γ介导的IDO表达刺激。最后，ido阳性il -32γ教育MΦs抑制CD4+T细胞增殖和IL-2、IFN-γ和TNF-α的产生。综上所述，我们的研究结果表明，来自MM细胞的IL-32γ促进MΦs的免疫抑制功能，是MM治疗的潜在靶点。
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.