Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression.
Cancer Lett
; 446: 38-48, 2019 04 01.
Article
em En
| MEDLINE
| ID: mdl-30660652
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interleucinas
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Comunicação Parácrina
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Indolamina-Pirrol 2,3,-Dioxigenase
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Tolerância Imunológica
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Macrófagos
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Mieloma Múltiplo
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article