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Cited by 242Immune cells in cancerCytokine Signaling Pathways and InteractionsTGF-β signaling in diseases

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Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression

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Fu, Xiao-Long, Duan, Wei, Su, Chong-Yu, Mao, Fang-Yuan, Lv, Yi-Ping, Teng, Yong-Sheng, Yu, Pei-Wu, Zhuang, Yuan, Zhao, Yong-Liang·2017·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-017-2052-5PMC PMC11028627
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Abstract

Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163+CD206+ M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163+CD206+ M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10 high TGF-β high IL-12 p35low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.

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Research works printed but not linked: 36

  1. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266 · DOI
  2. Verreck FA, de Boer T, Langenberg DM et al (2004) Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA 101:4560–4565 · DOI
  3. Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181:3733–3739 · DOI
  4. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173 · DOI · Paper page
  5. Satoh T, Takeuchi O, Vandenbon A et al (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11:936–944 · DOI · Paper page
  6. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555 · DOI · Paper page
  7. Mauer J, Chaurasia B, Goldau J et al (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430 · DOI · Paper page
  8. Rohleder N, Aringer M, Boentert M (2012) Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci 1261:88–96 · DOI · Paper page
  9. Aoki Y, Feldman GM, Tosato G (2003) Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101:1535–1542 · DOI
  10. Azare J, Doane A, Leslie K et al (2011) Stat3 mediates expression of autotaxin in breast cancer. PLoS One 6:e27851 · DOI
  11. Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX, Fang JY (2008) Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 10:287–297 · DOI
  12. Leeman RJ, Lui VWY, Grandis JR (2006) STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 6:231–241 · DOI
  13. Spence S, Fitzsimons A, Boyd CR et al (2013) Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization. Immunity 38:66–78 · DOI
  14. Zhuang Y, Peng LS, Zhao YL et al (2012) CD8(+) T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology 143:951–962 · DOI
  15. Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457 · DOI · Paper page
  16. Duluc D, Delneste Y, Tan F et al (2007) Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood 110:4319–4330 · DOI
  17. Mantovani A, Allavena P, Sica A (2004) Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer 40:1660–1667 · DOI
  18. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727 · DOI
  19. Hutchins AP, Poulain S, Miranda-Saavedra D (2012) Genome-wide analysis of STAT3 binding in vivo predicts effectors of the anti-inflammatory response in macrophages. Blood 119:E110–E119 · DOI
  20. Yan Y, Zhang J, Li JH, Liu X, Wang JZ, Qu HY, Wang JS, Duan XY (2016) High tumor-associated macrophages infiltration is associated with poor prognosis and may contribute to the phenomenon of epithelial–mesenchymal transition in gastric cancer. Onco Targets Ther 9:3975–3983 · DOI
  21. Yuan FJ, Fu X, Shi HF, Chen GP, Dong P, Zhang WY (2014) Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 Pathway. PLoS One 9:e107063 · DOI
  22. Hasita H, Komohara Y, Okabe H, Masuda T, Ohnishi K, Lei XF, Beppu T, Baba H, Takeya M (2010) Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci 101:1913–1919 · DOI
  23. Shiraishi D, Fujiwara Y, Komohara Y, Mizuta H, Takeya M (2012) Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys Res Commun 425:304–308 · DOI · Paper page
  24. Necula LG, Chivu-Economescu M, Stanciulescu EL et al (2012) IL-6 and IL-11 as markers for tumor aggressiveness and prognosis in gastric adenocarcinoma patients without mutations in Gp130 subunits. J Gastrointest Liver Dis 21:23–29
  25. Jinno T, Kawano S, Maruse Y et al (2015) Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma. Oncol Rep 33:2161–2168 · DOI
  26. Gao J, Zhao S, Halstensen TS (2016) Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep 35:3265–3274 · DOI
  27. Lin CN, Wang CJ, Chao YJ, Lai MD, Shan YS (2015) The significance of the co-existence of osteopontin and tumor-associated macrophages in gastric cancer progression. BMC Cancer 15:128 · DOI
  28. Sica A, Larghi P, Mancino A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355 · DOI · Paper page
  29. Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, Ganju RK, Satoskar AR (2014) CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model. Immunology 143:109–119 · DOI
  30. Tiainen S, Tumelius R, Rilla K, Hamalainen K, Tammi M, Tammi R, Kosma V-M, Oikari S, Auvinen P (2015) High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology 66:873–883 · DOI
  31. Hu H, Hang J-J, Han T, Zhuo M, Jiao F, Wang L-W (2016) The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer. Tumor Biol 37:8657–8664 · DOI
  32. Shen L, Li H, Shi Y, Wang D, Gong J, Xun J, Zhou S, Xiang R, Tan X (2016) M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Sci Rep 6:30347 · DOI
  33. Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, Lu J, Liu J (2013) Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat 12:259–267 · DOI
  34. Ryder M, Ghossein RA, Ricarte-Filho JCM, Knauf JA, Fagin JA (2008) Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer 15:1069–1074 · DOI
  35. Niino D, Komohara Y, Kimura Y et al (2010) Ratio of M2 macrophage expression is closely associated with poor prognosis for Angioimmunoblastic T-cell lymphoma (AITL). Pathol Int 60:278–283 · DOI
  36. Wang ZG, Si XL, Xu A et al (2013) Activation of STAT3 in human gastric cancer cells via interleukin (IL)-6-type cytokine signaling correlates with clinical implications. PLoS One 8:e75788 · DOI

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Metadata

Authors
Fu, X.-L., Duan, W., Su, C.-Y., Mao, F.-Y., Lv, Y.-P., Teng, Y.-S., Yu, P.-W., Zhuang, Y., & Zhao, Y.-L.
Affiliations
Army Medical University (CN)
Corresponding author
Zhuang, Yuan
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2017-08-21
Volume
66
Issue
12
Pages
1597-1608
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-017-2052-5
PMC
PMC11028627
OpenAlex
W2748596787
Cited by
242
References
0
Citations by year
2026: 31 · 2025: 34 · 2024: 32 · 2023: 32 · 2022: 26 · 2021: 37 · 2020: 26 · 2019: 15 · 2018: 9
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (unspecified)
Locations
  • Cancer Immunology Immunotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
interleukin-6, M2 macrophages, STAT3 phosphorylation, gastric cancer, tumor microenvironment, IL-10, TGF-beta, IL-12, tumor progression, tumor cell proliferation, tumor cell migration, prognostic factors
MeSH terms
Cell Differentiation, Cell Movement, Humans, Macrophages, Recombinant Proteins, Stomach Neoplasms, Transfection, Signal Transduction, Interleukin-6, Disease Progression, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor

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