Effects of IRF1 and IFN-β interaction on the M1 polarization of macrophages and its antitumor function

Abstract

Macrophages that differentiate from precursor monocytes can be polarized into a classically activated (M1) or alternatively activated (M2) status depending on different stimuli. Generally, interferon (IFN)-γ and lipopolysaccharide (LPS) are considered the classical stimuli with which to establish M1 polarization. IFN regulatory factor (IRF)1 and IFN-β are two crucial molecules involved in IFN-γ- and LPS-initialed signaling. However, the association between IRF1 and IFN-β in the context of the M1 polarization of macrophages is not yet fully understood. In this study, we demonstrate that U937-derived macrophages, in response to IFN-γ and LPS stimulation, readily acquire an M1 status, indicated by the increased expression of interleukin (IL)-12, IL-6, IL-23, tumor necrosis factor (TNF)-α and the M1-specific cell surface antigen, CD86, and the decreased expression of the M2-specific mannose receptor, CD206. However, the knockdown of IRF1 in U937-derived macrophages led to an impaired M1 status, as indicated by the decreased expression of the above-mentioned M1 markers, and the increased expression of the M2 markers, CD206 and IL-10. A similar phenomenon was observed in the M1 macrophages in which IFN-β was inhibited. Furthermore, we demonstrated that IRF1 and IFN-β may interact with each other in the IFN-γ- and LPS-initiated signaling pathway, and contribute to the IRF5 regulation of M1 macrophages. In addition, the conditioned medium collected from the M1 macrophages in which IRF1 or IFN-β were inhibited, exerted pro-tumor effects on the HepG2 and SMMC-7721 cells, as indicated by an increase in proliferation, the inhibition of apoptosis and an enhanced invasion capability. The findings of our study suggest that the interactions of IRF1, IFN-β and IRF5 are involved in the M1 polarization of macro phages and have antitumor functions. These data may provide a novel antitumor strategy for targeted cancer therapy.

Interferon Lambda Genetics and Biology in Regulation of Viral Control

“…Type I IFN promotes the polarization of macrophages to an inflammatory “M1” phenotype and increases the production of nitric oxide ( 73 , 123 – 125 ). Type I IFN also enhances DC function by promoting their generation from monocytic precursors and leads to upregulation of MHC and costimulatory molecules in addition to increasing IL-12 production and enhancing DC migration ( 2 , 126 , 127 ).…”

The effects of CD14 and IL-27 on induction of endotoxin tolerance in human monocytes and macrophages

“…M1 macrophages produce proinflammatory TNF-␣ (85), which can subsequently shift cells to a more M2-like phenotype, inducing TNF tolerance (72). In addition, IFN-␤ produced in response to LPS is involved in promoting macrophages to the M1 phenotype (86). There are conflicting reports on the role of IFN-␤ in endotoxin tolerance; endotoxin tolerance occurs independent of IFN-␤ production in IFNAR knock-out mice (87), whereas IFN-␤ production has also been attributed to the development of sepsis in murine models, suggesting an association between a refractory state of monocytes and low IFN-␤ production (88).…”

Treatment with TNF-α inhibitor rectifies M1 macrophage polarization from blood CD14+ monocytes in patients with psoriasis independent of STAT1 and IRF-1 activation

“…IRF-1 subsequently induced M1 polarization in inflammatory microenvironments [21]. In contrast, M1 macrophages were decreased and M2 macrophages were increased after the IRF-1 knockdown [22]. Mechanically, IRF-1 suppressed the binding of other transcription factors to the IL-4 promoter, which thus inhibited M2 macrophage activation [23].…”