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

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)-gamma and lipopolysaccharide ( LPS) are considered the classical stimuli with which to establish M1 polarization. IFN regulatory factor (IRF) 1 and IFN-beta are two crucial molecules involved in IFN-gamma- and LPS-initialed signaling. However, the association between IRF1 and IFN-beta 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-gamma 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)-alpha 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-beta was inhibited. Furthermore, we demonstrated that IRF1 and IFN-beta may interact with each other in the IFN-gamma-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-beta 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-beta 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.