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

Xie,Changli; Liu,Cuiying; Wu,Bitao; Lin,Yan; Ma,Tingting; Xiong,Haiyu; Wang,Qin; Li,Ziwei; Ma,Chenyu; Tu,Zhiguang

doi:10.3892/ijmm.2016.2583

July-2016 Volume 38 Issue 1

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July-2016 Volume 38 Issue 1

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Article Open Access

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

Authors:
- Changli Xie
- Cuiying Liu
- Bitao Wu
- Yan Lin
- Tingting Ma
- Haiyu Xiong
- Qin Wang
- Ziwei Li
- Chenyu Ma
- Zhiguang Tu
View Affiliations / Copyright

Affiliations: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China

Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 148-160
|
Published online on: May 10, 2016

https://doi.org/10.3892/ijmm.2016.2583
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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.

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1	Das A, Sinha M, Datta S, Abas M, Chaffee S, Sen CK and Roy S: Monocyte and macrophage plasticity in tissue repair and regeneration. Am J Pathol. 185:2596–606. 2015. View Article : Google Scholar : PubMed/NCBI
2	Murray PJ and Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 11:723–737. 2011. View Article : Google Scholar : PubMed/NCBI
3	Lawrence T and Natoli G: Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 11:750–761. 2011. View Article : Google Scholar : PubMed/NCBI
4	Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI
5	Duluc D, Corvaisier M, Blanchard S, Catala L, Descamps P, Gamelin E, Ponsoda S, Delneste Y, Hebbar M and Jeannin P: Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int J Cancer. 125:367–373. 2009. View Article : Google Scholar : PubMed/NCBI
6	Labonte AC, Tosello-Trampont AC and Hahn YS: The role of macrophage polarization in infectious and inflammatory diseases. Mol Cells. 37:275–285. 2014. View Article : Google Scholar : PubMed/NCBI
7	Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA and Orekhov AN: Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol. 184:436–445. 2015. View Article : Google Scholar : PubMed/NCBI
8	Melton DW, McManus LM, Gelfond JA and Shireman PK: Temporal phenotypic features distinguish polarized macrophages in vitro. Autoimmunity. 48:161–176. 2015. View Article : Google Scholar : PubMed/NCBI
9	Biswas SK and Mantovani A: Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 11:889–896. 2010. View Article : Google Scholar : PubMed/NCBI
10	Chabot S, Charlet D, Wilson TL and Yong VW and Yong VW: Cytokine production consequent to T cell - microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. J Neurosci Methods. 105:111–120. 2001. View Article : Google Scholar : PubMed/NCBI
11	Dall'Asta M, Derlindati E, Ardigò D, Zavaroni I, Brighenti F and Del Rio D: Macrophage polarization: The answer to the diet/inflammation conundrum? Nutr Metab Cardiovasc Dis. 22:387–392. 2012. View Article : Google Scholar : PubMed/NCBI
12	Ohashi W, Hattori K and Hattori Y: Control of macrophage dynamics as a potential therapeutic approach for clinical disorders involving chronic inflammation. J Pharmacol Exp Ther. 354:240–250. 2015. View Article : Google Scholar : PubMed/NCBI
13	Heusinkveld M and van der Burg SH: Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med. 9:2162011. View Article : Google Scholar : PubMed/NCBI
14	Bögels M, Braster R, Nijland PG, Gül N, van de Luijtgaarden W, Fijneman RJ, Meijer GA, Jimenez CR, Beelen RH and van Egmond M: Carcinoma origin dictates differential skewing of monocyte function. OncoImmunology. 1:798–809. 2012. View Article : Google Scholar : PubMed/NCBI
15	Pollard JW: Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol. 84:623–630. 2008. View Article : Google Scholar : PubMed/NCBI
16	Tugal D, Liao X and Jain MK: Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol. 33:1135–1144. 2013. View Article : Google Scholar : PubMed/NCBI
17	Gough DJ, Levy DE, Johnstone RW and Clarke CJ: IFNgamma signaling - does it mean JAK-STAT? Cytokine Growth Factor Rev. 19:383–394. 2008. View Article : Google Scholar : PubMed/NCBI
18	Jaruga B, Hong F, Kim WH and Gao B: IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. Am J Physiol Gastrointest Liver Physiol. 287:G1044–G1052. 2004. View Article : Google Scholar : PubMed/NCBI
19	Martinez FO, Gordon S, Locati M and Mantovani A: Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 177:7303–7311. 2006. View Article : Google Scholar : PubMed/NCBI
20	Negishi H, Fujita Y, Yanai H, Sakaguchi S, Ouyang X, Shinohara M, Takayanagi H, Ohba Y, Taniguchi T and Honda K: Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc Natl Acad Sci USA. 103:15136–15141. 2006. View Article : Google Scholar : PubMed/NCBI
21	Liu J, Guan X, Tamura T, Ozato K and Ma X: Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. J Biol Chem. 279:55609–55617. 2004. View Article : Google Scholar : PubMed/NCBI
22	Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T and Honda K: Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem Biophys Res Commun. 354:1045–1051. 2007. View Article : Google Scholar : PubMed/NCBI
23	Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, Williams BR, Major J, Hamilton TA, Fenton MJ and Vogel SN: TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol. 3:392–398. 2002. View Article : Google Scholar : PubMed/NCBI
24	Fleetwood AJ, Dinh H, Cook AD, Hertzog PJ and Hamilton JA: GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol. 86:411–421. 2009. View Article : Google Scholar : PubMed/NCBI
25	Reis LF, Harada H, Wolchok JD, Taniguchi T and Vilcek J: Critical role of a common transcription factor, IRF-1, in the regulation of IFN-beta and IFN-inducible genes. EMBO J. 11:185–193. 1992.PubMed/NCBI
26	Guo Z, Garg S, Hill KM, Jayashankar L, Mooney MR, Hoelscher M, Katz JM, Boss JM and Sambhara S: A distal regulatory region is required for constitutive and IFN-beta-induced expression of murine TLR9 gene. J Immunol. 175:7407–7418. 2005. View Article : Google Scholar : PubMed/NCBI
27	Liu J, Cao S, Herman LM and Ma X: Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. J Exp Med. 198:1265–1276. 2003. View Article : Google Scholar : PubMed/NCBI
28	Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M and Udalova IA: IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 12:231–238. 2011. View Article : Google Scholar : PubMed/NCBI
29	Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG, et al: Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med. 21:610–618. 2015. View Article : Google Scholar : PubMed/NCBI
30	Feng D, Sangster-Guity N, Stone R, Korczeniewska J, Mancl ME, Fitzgerald-Bocarsly P and Barnes BJ: Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression. J Immunol. 185:6003–6012. 2010. View Article : Google Scholar : PubMed/NCBI
31	Mancl ME, Hu G, Sangster-Guity N, Olshalsky SL, Hoops K, Fitzgerald-Bocarsly P, Pitha PM, Pinder K and Barnes BJ: Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. J Biol Chem. 280:21078–21090. 2005. View Article : Google Scholar : PubMed/NCBI
32	Tan RS, Taniguchi T and Harada H: Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Res. 56:2417–2421. 1996.PubMed/NCBI
33	Zimmermann A, Trilling M, Wagner M, Wilborn M, Bubic I, Jonjic S, Koszinowski U and Hengel H: A cytomegaloviral protein reveals a dual role for STAT2 in IFN-(gamma) signaling and antiviral responses. J Exp Med. 201:1543–1553. 2005. View Article : Google Scholar : PubMed/NCBI
34	Steen HC and Gamero AM: The role of signal transducer and activator of transcription-2 in the interferon response. J Interferon Cytokine Res. 32:103–110. 2012. View Article : Google Scholar : PubMed/NCBI
35	Taniguchi K, Hikiji H, Okinaga T, Hashidate-Yoshida T, Shindou H, Ariyoshi W, Shimizu T, Tominaga K and Nishihara T: Essential role of lysophosphatidylcholine acyltransferase 3 in the induction of macrophage polarization in PMA-treated U937 cells. J Cell Biochem. 116:2840–2848. 2015. View Article : Google Scholar : PubMed/NCBI
36	Maeß MB, Wittig B, Cignarella A and Lorkowski S: Reduced PMA enhances the responsiveness of transfected THP-1 macrophages to polarizing stimuli. J Immunol Methods. 402:76–81. 2014. View Article : Google Scholar
37	El Fiky A, Perreault R, McGinnis GJ and Rabin RL: Attenuated expression of interferon-β and interferon-λ1 by human alternatively activated macrophages. Hum Immunol. 74:1524–1530. 2013. View Article : Google Scholar : PubMed/NCBI
38	Stout RD, Watkins SK and Suttles J: Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 86:1105–1109. 2009. View Article : Google Scholar : PubMed/NCBI
39	Siveen KS and Kuttan G: Role of macrophages in tumour progression. Immunol Lett. 123:97–102. 2009. View Article : Google Scholar : PubMed/NCBI
40	Jensen MA and Niewold TB: Interferon regulatory factors: critical mediators of human lupus. Transl Res. 165:283–295. 2015. View Article : Google Scholar :
41	Paun A and Pitha PM: The IRF family, revisited. Biochimie. 89:744–753. 2007. View Article : Google Scholar : PubMed/NCBI
42	Salloum R and Niewold TB: Interferon regulatory factors in human lupus pathogenesis. Transl Res. 157:326–331. 2011. View Article : Google Scholar : PubMed/NCBI
43	Günthner R and Anders HJ: Interferon-regulatory factors determine macrophage phenotype polarization. Mediators Inflamm. 2013:7310232013. View Article : Google Scholar :
44	Jaguin M, Houlbert N, Fardel O and Lecureur V: Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 281:51–61. 2013. View Article : Google Scholar : PubMed/NCBI
45	Duechler M, Peczek L, Zuk K, Zalesna I, Jeziorski A and Czyz M: The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes. Immunobiology. 219:158–165. 2014. View Article : Google Scholar
46	Nicolini A, Carpi A and Rossi G: Cytokines in breast cancer. Cytokine Growth Factor Rev. 17:325–337. 2006. View Article : Google Scholar : PubMed/NCBI
47	Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, Hu XB, Zheng MH, Liang L, Feng L, et al: Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70:4840–4849. 2010. View Article : Google Scholar : PubMed/NCBI
48	Buijs JT, Stayrook KR and Guise TA: TGF-β in the bone microenvironment: role in breast cancer metastases. Cancer Microenviron. 4:261–281. 2011. View Article : Google Scholar : PubMed/NCBI
49	Drabsch Y and ten Dijke P: TGF-β signaling in breast cancer cell invasion and bone metastasis. J Mammary Gland Biol Neoplasia. 16:97–108. 2011. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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