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Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression
Open accessAbstract
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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“IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3 (215, 216).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [216]
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Cited by
Sorted by citations
Macrophages in immunoregulation and therapeutics
Chen, S., Saeed, A. F. U. H., Liu, Q., Jiang, Q., Xu, H., Xiao, G. G., Rao, L., & Duo, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01452-1 · Cited by 2,477
“IFN-γ ligand binding to its receptor induces Janus kinase 1/2-mediated tyrosine phosphorylation and subsequent dimerization and activation of STAT1, which binds as a homodimer to the promoter of M1 signature genes.184 Activation of STAT3 by IL-10 and IL-6 stimulation can induce M2-associated markers expression such as…”
BackgroundIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453
“IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3 (215, 216).”
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Basak, U., Sarkar, T., Mukherjee, S., Chakraborty, S., Dutta, A., Dutta, S., Nayak, D., Kaushik, S., Das, T., & Sa, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1295257 · Cited by 356
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“Indeed, previous studies have shown that IL6 induces profibrotic macrophage differentiation (41,42).”
BackgroundRole of exosomes in the immune microenvironment of ovarian cancer (Review)
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Jiang, B., Zhu, S.-H., Xiao, S., & Xue, M. (2019) · Inflammation · doi:10.1007/s10753-019-01004-2 · Cited by 43
Yang, H., Xu, H., Wang, Z., Li, X., Wang, P., Cao, X., Xu, Z., Lv, D., Rong, Y., Chen, M., et al. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110573 · Cited by 45
The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis
Debacker, J., Gondry, O., Lahoutte, T., Keyaerts, M., & Huvenne, W. (2021) · Cancers · doi:10.3390/cancers13143422 · Cited by 39
CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3
Zhao, C.-R., Zeng, N., Zhou, X.-M., Tan, Y.-F., Wang, Y.-C., Zhang, J., Wu, Y.-P., & Zhang, Q. (2023) · BMC Cancer · doi:10.1186/s12885-023-10826-1 · Cited by 38
“In the immune system, IL-6 has a dual effect: a pro-inflammatory or an anti-inflammatory factor, mainly depending on the local immune microenvironment [17, 27].”
BackgroundMoonlighting Proteins Are Important Players in Cancer Immunology
Adamo, A., Frusteri, C., Pallotta, M. T., Pirali, T., Sartoris, S., & Ugel, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613069 · Cited by 41
“Tgase2 inhibitors have shown to prevent tubule formation and such phenotype can be restored by exogenous TGF-b1.”
BackgroundInfluentialPrognostic Biomarkers in Evolving Melanoma Immunotherapy
Reschke, R., Enk, A. H., & Hassel, J. C. (2024) · American Journal of Clinical Dermatology · doi:10.1007/s40257-024-00910-y · Cited by 37
“Additionally, epithelial cells can produce interleukin-6, which promotes an M2 macrophage phenotype [46, 47].”
Carbon Dots Crosslinked Egg White Hydrogel for Tissue Engineering
Wu, J., Lei, J., Li, M.-X., Zhang, A., Li, Y., Liang, X., de Souza, S. C., Yuan, Z., Wang, C.-M., Chen, G.-K., et al. (2024) · Advancement of science · doi:10.1002/advs.202404702 · Cited by 34
El‐Asrar, A. M. A., Ahmad, A., Allegaert, E., Siddiquei, M. M., Gikandi, P. W., Hertogh, G. D., & Opdenakker, G. (2019) · Ocular Immunology and Inflammation · doi:10.1080/09273948.2019.1616772 · Cited by 38
“STAT3 and its downstream genes promote cancer growth, survival, angiogenesis and metastasis.(66) Similarly, signaling pathways mediated by STAT3 play a primary role in diabetic retinopathy progression.”
BackgroundThe lactylation-macrophage interplay: implications for gastrointestinal disease therapeutics
Che, X., Zhang, Y., Chen, X., Xie, G., Li, J., Xu, C., Zhang, C., Zhu, Y., & Yang, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1608115 · Cited by 26
Targeting crosstalk of STAT3 between tumor-associated M2 macrophages and Tregs in colorectal cancer
Huang, L.-L., Zhao, Y., Shan, M., Wang, S., Chen, J., Liu, Z., & Xu, Q. (2023) · Cancer Biology & Therapy · doi:10.1080/15384047.2023.2226418 · Cited by 31
Self-citationRole of IL-37 in Cardiovascular Disease Inflammation.
Yang, Z., Kang, L.-P., Wang, Y., Xiang, J., Wu, Q., Xu, C., Zhou, Y.-Q., Chen, S.-Y., Fang, H.-C., Liu, J., et al. (2019) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2019.04.007 · Cited by 31
Wang, Z., Kun, Y., Жао, Л., Wen, D., Lin, P., & Jibo, W. (2021) · Cell Cycle · doi:10.1080/15384101.2020.1867788 · Cited by 35
“Based on previous research, IL-6 induces macrophage to differentiate into M2 for inhibiting inflammation [33,34].”
MethodTiong, T.-Y., Chan, M., Wang, C., Yadav, V. K., Pikatan, N. W., Fong, I.-H., Yeh, C.-T., Kuo, K.-T., & Huang, W.-C. (2023) · Life Science · doi:10.1016/j.lfs.2023.121945 · Cited by 28
Wei, R.-Y., Song, J.-Q., Pan, H., Liu, X.-W., & Gao, J.-P. (2024) · Oncoimmunology · doi:10.1080/2162402x.2024.2352179 · Cited by 27
“Given the crucial role of adjuvant therapy in patients with advanced GC, 2 we examined the correlation between CPT1C + CAFs infiltration and treatment efficacy.”
BackgroundInfluentialCancer invasion and anaerobic bacteria: new insights into mechanisms
Hurst, R., Brewer, D. S., Gihawi, A., Wain, J. R., & Cooper, C. S. (2024) · Journal of Medical Microbiology · doi:10.1099/jmm.0.001817 · Cited by 29
Griffiths, J. I., Cosgrove, P. A., Medina, E. F., Nath, A., Chen, J., Adler, F. R., Chang, J. T., Khan, Q. J., & Bild, A. H. (2025) · Nature Communications · doi:10.1038/s41467-025-56279-x · Cited by 29
Recent advances in potential targets for myocardial ischemia reperfusion injury: Role of macrophages
Zhuang, Q., Li, M., Hu, D., & Li, J. (2024) · Molecular Immunology · doi:10.1016/j.molimm.2024.02.007 · Cited by 28
Niu, X., Zhu, Z., & Bao, J. (2020) · Cancer Cell International · doi:10.1186/s12935-021-01813-2 · Cited by 26
“The decreased level of albumin correlated with the production of pro-inflammatory cytokines, such as interleukin-6, a cytokine associated with progression of cancers [32].”
BackgroundMartin, D., Rödel, F., Balermpas, P., Winkelmann, R., Fokas, E., & Rödel, C. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01200 · Cited by 26
“Interleukin 6 upregulates tumor-promoting M2 macrophages via either STAT3 phosphorylation (40) or direct inhibition of apoptosis and stimulation of proliferation, also mainly mediated by STAT3 (41).”
BackgroundBurger, B., Kühl, C. M. C., Candreva, T., Cardoso, R. D. S., Silva, J. R., Castelucci, B. G., Consonni, S. R., Fisk, H. L., Calder, P. C., Vinolo, M. A. R., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45508-1 · Cited by 30
The Complex Role of Thrombin in Cancer and Metastasis: Focus on Interactions with the Immune System
Aleksandrowicz, K., Hempel, D., Polityńska, B., Wojtukiewicz, A. M., Honn, K. V., Tang, D. G., & Wojtukiewicz, M. Z. (2023) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0043-1776875 · Cited by 26
“26,33 M2 macrophages, through the secretion of aginase-1, IL-10, and TGF-β , reduce the immunogenicity of the tumor.”
BackgroundReicherz, A., Eltit, F., Scotland, K. B., Almutairi, K., Bell, R. H., Mojtahedzadeh, B., Cox, M. E., Chew, B., & Lange, D. (2023) · Scientific Reports · doi:10.1038/s41598-023-31885-1 · Cited by 25
“Urothelium 47 (10) 67 (25) 47 (22) 41 (5) 44 (5) 0.”
Jiménez-Uribe, A., Valencia-Martínez, H., Carballo-Uicab, G., Vallejo-Castillo, L., Medina-Rivero, E., Chacón-Salinas, R., Pavón, L., Velasco-Velázquez, M., Mellado-Sánchez, G., Estrada-Parra, S., et al. (2019) · Journal of Immunological Research · doi:10.1155/2019/2198508 · Cited by 25
“As an immunomodulatory cytokine, IL-6 has been related to tissue remodeling and macrophage polarization to M2 profile [40, 41].”
An, W., Yu, Y., Zhang, Y., Zhang, Z., Yu, Y., & Zhao, X. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14549 · Cited by 30
“STAT3 is considered to be one of the primary signalling molecules for M2 macrophage polarization (Yang et al., 2012; Fu et al., 2017), and this transcription factor is also selectively activated by M2 macrophage-polarizing cytokines, such as IL-10, IL-4 and IL-13 (Sica and Bronte, 2007).”
BackgroundLiu, H., Yang, X.-C., Liu, D.-C., Tong, C., Wen, W., & Chen, R.-H. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1156006 · Cited by 22
“In addition, serum albumin plays an important role in inhibiting the production of pro-inflammatory cytokines and enhancing cell-mediated immunity (51).”
BackgroundImmunomodulatory role of thrombin in cancer progression
Alexander, E. T., & Gilmour, S. K. (2022) · Molecular Carcinogenesis · doi:10.1002/mc.23398 · Cited by 32
“microenvironment promotes the polarization of immunosuppressive M2 macrophages over that of pro‐inflammatory M1 macrophages.(88,89) Tumor‐associated M2 macrophages not only promote”
BackgroundThe multi-faceted immune modulatory role of S100A4 in cancer and chronic inflammatory disease
Wong, T. K. S., Kang, R., & Yun, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1525567 · Cited by 20
Prognostic value of CD163+ macrophages in solid tumor malignancies: A scoping review
Mathiesen, H., Juul‐Madsen, K., Tramm, T., Vorup‐Jensen, T., Møller, H. J., Etzerodt, A., & Andersen, M. N. (2025) · Immunology Letters · doi:10.1016/j.imlet.2025.106970 · Cited by 23
Ganguly, K., Shah, A., Atri, P., Rauth, S., Ponnusamy, M. P., Sushil Kumar, K., & Batra, S. K. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.022 · Cited by 25
Yang, J.-K., & Xing, Z.-Y. (2021) · Experimental biology and medicine · doi:10.1177/15353702211010420 · Cited by 22
Kewcharoenwong, C., Prabowo, S. A., Bancroft, G. J., Fletcher, H. A., & Lertmemongkolchai, G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02109 · Cited by 25
“IL-6 can induce M2 macrophage differentiation through STAT3 activation and can enhance infiltration of CD163+CD206+macrophages in gastric tumor tissue (54).”
BackgroundHe, F.-F., Bao, D., Su, H., Wang, Y.-M., Lei, C., Zhang, C.-Y., Ye, C., Tang, H., Wan, C., You, C., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26546 · Cited by 22
“Not surprisingly, by immunoblotting it is showed that IL6 raises the expression of phosphorylated STAT3 and that is in line with studies from other cell lines (Fu et al., 2017).”
ResultShimizu, D., Kanda, M., & Kodera, Y. (2018) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v10.i6.124 · Cited by 23
Zhang, X., Zhu, M., Hong, Z., & Chen, C. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-1256 · Cited by 23
Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation
Ito, A., Kagawa, S., Sakamoto, S., Kuwada, K., Kajioka, H., Yoshimoto, M., Kikuchi, S., Kuroda, S., Yoshida, R., Tazawa, H., et al. (2021) · BMC Cancer · doi:10.1186/s12885-021-07816-6 · Cited by 21
“STAT3 is commonly activated in tumor-infiltrating macrophages [48, 49], and STAT3 can bind to the promoter of the CD274 gene required for PD-L1 gene expression in T-cell lymphoma [38, 50].”
BackgroundMak, T.-K., Li, K., Zhao, Z., Wang, K.-X., Zeng, L.-L., He, Q., Lu, W.-Q., Chen, W., He, Y.-L., Li, J., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217422 · Cited by 20
Su, P., Tian, Y., Zhang, Y., Huang, H., Chen, M., Cao, C., Kang, W., Liu, Y., & Yu, J. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03453-8 · Cited by 22
“IL-6 could induce macrophages differentiation into the pro-tumor M2 phenotype via activating STAT3 phosphorylation and then promote GC cells proliferation and migration [41].”
BackgroundM2 macrophages participate in ILC2 activation induced by Helicobacter pylori infection
Peng, R., Xu, C., Zhang, L., Liu, X., Peng, D., Chen, X., Liu, D., & Li, R. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2347025 · Cited by 25
“32,33 Our findings indicated that H. pylori infection could promote the polarization of macrophages to M2.”
BackgroundOh, J., Hwa, C., Jang, D., Shin, S., Lee, S., Kim, J., Lee, S. E., Jung, H. R., Oh, Y., Jang, G., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00795-z · Cited by 21
Classic and new mediators for in vitro modelling of human macrophages
Luque-Martin, R., Mander, P. K., Leenen, P. J. M., & de Winther, M. P. J. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ru0620-018r · Cited by 24
Panipinto, P. M., Singh, A. K., Shaikh, F. S., Siegel, R., Chourasia, M., & Ahmed, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212580 · Cited by 19
“While these results are open to different interpretations, the available literature detailing the role of STAT3 in LPS-induced TNFα and other forms of chemokine production in macrophage cells [38,39] further attest to our argument that takinib elicits its anti-inflammatory effects primarily through suppression of JAK/…”
ResultAnghel, F. M., Matei, S.-C., Olteanu, G., Barna, R. A., & Marian, C. (2025) · Biomedicines · doi:10.3390/biomedicines13123050 · Cited by 24
Pang, H., Dai, L., Chen, L., Chen, X., Chen, Z., Zhang, S.-R., & Sun, H. (2024) · BMC Cancer · doi:10.1186/s12885-024-12349-9 · Cited by 18
“In addition, a low serum albumin has been confirmed to prompt the production of pro-inflammatory cytokines and reduce cell-mediated immunity [35].”
BackgroundLi, J., Bao, Y., Peng, S.-S., Jiang, C., Zhu, L., Zou, S.-H., Xu, J.-J., & Li, Y. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45060314 · Cited by 18
“The promoting effect of M2 macrophages on the development of tumors has been confirmed in many reports, including gastric cancer and OSCC [8,9].”
BackgroundChen, F., Xie, C., Ren, K., & Xu, X. (2023) · Nutrition and Cancer · doi:10.1080/01635581.2023.2212426 · Cited by 20
“The decreased level of serum albumin may be mediated by proinflammatory cytokines, such as interleukin-6, which is highly expressed in tumor tissues and is associated with cancer progression (33, 34).”
BackgroundChoi, H., Yang, S.-W., Joo, J., Park, M., Jin, Y.-H., Kim, J.-W., Lee, S.-Y., Lee, S.-V., Yun, T.-J., Cho, M., et al. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109215 · Cited by 18
Shan, Z., Yan, Z.-B., Peng, L.-S., Cheng, P., Teng, Y.-S., Mao, F.-Y., Fan, K., Zhuang, Y., & Zhao, Y.-L. (2021) · Journal of Immunological Research · doi:10.1155/2021/6613247 · Cited by 18
“Firstly, we confirmed that tumorinfiltrating neutrophils exhibited an activated phenotype characterized by the increase of molecule CD54, compared with peripheral cohorts [21].”
BackgroundMethodSelf-citationThe role of tumor-associated macrophages in lung cancer
Zhu, R., Huang, J., & Qian, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1556209 · Cited by 23
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
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2017-08-21
- Volume
- 66
- Issue
- 12
- Pages
- 1597-1608
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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