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. 2021 Apr 23:2021:5535578.
doi: 10.1155/2021/5535578. eCollection 2021.

IL-6 Promotes the Proliferation and Immunosuppressive Function of Myeloid-Derived Suppressor Cells via the MAPK Signaling Pathway in Bladder Cancer

Zhong Zheng  1 , Xinyi Zheng  2 , Yiwen Zhu  3 , Zhixian Yao  1 , Weiguang Zhao  1 , Youjia Zhu  4 , Feng Sun  1 , Xingyu Mu  1 , Yong Wang  5 , Wanqing He  6 , Zhihong Liu  1 , Ke Wu  1 , Junhua Zheng  1
Affiliations

IL-6 Promotes the Proliferation and Immunosuppressive Function of Myeloid-Derived Suppressor Cells via the MAPK Signaling Pathway in Bladder Cancer

Zhong Zheng et al. Biomed Res Int. .

Abstract

Muscle-invasive bladder cancer (MIBC) is characterized by a highly complex immune environment, which is not well understood. Interleukin-6 (IL-6) is generated and secreted by multifarious types of cells, including tumor cells. This study was aimed at demonstrating that the levels of IL-6 and the number of myeloid-derived suppressor cells (MDSCs), with a positive correlation between them, increased in MIBC tissues, promoting MIBC cell proliferation, especially in patients with recurrence. In coculture analysis, MDSCs, with the stimulation of IL-6, could significantly lower the proliferation ability of CD4+ or CD8+ T lymphocytes. Further, this study demonstrated that IL-6 could upregulate the mitogen-activated protein kinase (MAPK) signaling pathway in MDSCs. The MAPK signaling inhibitor, aloesin, partially reversed the effects of IL-6 on MDSCs. These data suggested that IL-6 promoted MIBC progression by not only accelerating proliferation but also improving the immune suppression ability of MDSCs through activating the MAPK signaling pathway.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Interleukin 6 (IL-6) levels increased in muscle-invasive bladder cancer (MIBC) and promoted cancer progression. (a) IL-6 levels in MIBC tissues and normal urothelium determined by the enzyme-linked immunosorbent assay (ELISA). (b) Immunochemistry results for IL-6 in MIBC tissues and normal urothelium. (c) IL-6 levels in MIBC tissues and recurrent MIBC determined by ELISA. (d) Immunochemistry results for IL-6 in MIBC tissues and recurrent MIBC. (e) Prognosis of patients with high or low IL-6 expression according to TCGA database. (f) MIBC tumor volume with or without IL-6 treatment (n = 10). (g) Tumor weight with or without IL-6 treatment (n = 10). (h) Survival time for mice with MIBC with or without IL-6 treatment (n = 10). Mean ± SD, ∗∗P < 0.01, ∗∗∗P < 0.005, and ∗∗∗∗P < 0.001.
Figure 2
Figure 2
Myeloid-derived suppressor cells (MDSCs) increased in MIBC tissues and promoted cancer progression. (a, b) Flow cytometry and statistical analysis of the proportion of MDSCs in MIBC tissues and normal urothelium from 200 patients. (c, d) Flow cytometry and statistical analysis of the proportion of MDSCs in recurrent MIBC tissues and in MIBC tissues. (e) Tumor growth rates in a MIBC mouse model with or without MDSC treatment (n = 10). (f) Tumor weight in a MIBC mouse model with or without MDSC treatment (n = 10). (g) Survival time of a MIBC mouse model with or without MDSC treatment (n = 10). Mean ± SD, ∗∗∗P < 0.005, and ∗∗∗∗P < 0.001.
Figure 3
Figure 3
IL-6 promoted MDSC proliferation in MIBC tissues. (a, b) Correlation between IL-6 (AOD and MFI) and MDSCs in MIBC tissues. (c) Experimental design of MDSC extraction and IL-6 treatment. (d) CCK-8 assays were used to test MDSCs with or without IL-6 treatment. (e) MDSC proliferation rates were evaluated according to fluorescence attenuation. (f, g) Flow cytometry images and statistical analysis of MDSCs from humans and mice with or without IL-6 treatment. Mean ± SD, ∗∗∗P < 0.005, and ∗∗∗∗P < 0.001. AOD: average optical density; MFI: median fluorescence intensity.
Figure 4
Figure 4
IL-6 improved the immune-suppressive effects of MDSCs. (a) Experimental diagram of MDSC extraction and IL-6 treatment. (b–e) RT-PCR was used to evaluate Arg1 and iNOS levels in MDSCs with or without IL-6 treatment. (f–i) Summary of the suppressive effect of MDSCs by coculture with CD8+ T cells and CD4+ T cells at 1 : 4 and 1 : 2 ratios. Mean ± SD, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.005, and ∗∗∗∗P < 0.001. ns: no statistical significance.
Figure 5
Figure 5
IL-6 activated the mitogen-activated protein kinase (MAPK) signaling pathway in MDSCs. (a, b) Heat map of RNA sequencing results to evaluate differentially expressed genes in MDSCs with or without IL-6 treatment. (c, d) Differentially expressed genes were enriched for several signaling pathways. (e, f) Phosphorylation of critical proteins in the MAPK signaling pathway (MEK2, ERK, and MNK1) was evaluated by western blotting. (g–i) Intensity ratio of each band. Mean ± SD, ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005.
Figure 6
Figure 6
IL-6 promoted MDSC proliferation and immune-suppressive effects by activating the MAPK signaling pathway. (a) CCK-8 assays were used to evaluate MDSCs with or without IL-6 and/or aloesin treatment. (b) MDSC proliferation rates were evaluated according to fluorescence attenuation after IL-6 and/or aloesin treatment. (c–f) RT-PCR was used to evaluate Arg1 and iNOS levels in MDSCs with or without IL-6 and/or aloesin treatment. (g–j) Summary of the suppressive effect of MDSCs by coculture with CD8+ T cells and CD4+ T cells at 1 : 4 ratios. Mean ± SD, ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.005.
Figure 7
Figure 7
Schematic model. IL-6 promotes the proliferation and immunosuppressive function of MDSCs via the MAPK signaling pathway in MIBC.
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References

    1. Mahdavifar N., Ghoncheh M., Pakzad R., Momenimovahed Z., Salehiniya H. Epidemiology, incidence and mortality of bladder cancer and their relationship with the development index in the world. Asian Pacific Journal of Cancer Prevention. 2016;17(1):381–386. doi: 10.7314/apjcp.2016.17.1.381. - DOI - PubMed
    1. Klotz L., Brausi M. A. World Urologic Oncology Federation Bladder Cancer Prevention Program: a global initiative. Urologic Oncology. 2015;33(1):25–29. doi: 10.1016/j.urolonc.2014.07.017. - DOI - PubMed
    1. Lei S., Xu H., Chen N., et al. MKP-1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway. Oncology Letters. 2020;20(2):1743–1751. doi: 10.3892/ol.2020.11741. - DOI - PMC - PubMed
    1. Crispen P. L., Kusmartsev S. Mechanisms of immune evasion in bladder cancer. Cancer Immunology, Immunotherapy. 2020;69(1):3–14. doi: 10.1007/s00262-019-02443-4. - DOI - PMC - PubMed
    1. Schneider A. K., Chevalier M. F., Derré L. The multifaceted immune regulation of bladder cancer. Nature Reviews. Urology. 2019;16(10):613–630. doi: 10.1038/s41585-019-0226-y. - DOI - PubMed

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