title: 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 macrophages and have antitumor functions. These data may provide a novel antitumor strategy for targeted cancer therapy.
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Changli
authors.initials: C
authors.lastname: Xie
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Bitao
authors.initials: B
authors.lastname: Wu
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ma
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Ma
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D016764:Cell Polarity; D017077:Culture Media, Conditioned / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D017077:Culture Media, Conditioned; C494257:IRF1 protein, human; C431713:IRF5 protein, human; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D016899:Interferon-beta; D007371:Interferon-gamma