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

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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-10highTGF-βhighIL-12 lowp35 ) 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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Abbreviations

Bcl-xL:

B-cell lymphoma-extra large

CCK8:

Cell counting kit 8

CCL2:

Chemokine (C–C motif) ligand 2

GC:

Gastric cancer

M-CSF:

Macrophage colony-stimulating factor

PBMC:

Peripheral blood mononuclear cell

p-STAT3:

Phosphorylated STAT3

PVDF:

Polyvinylidene difluoride

SEM:

Standard error of mean

siRNA:

Small interfering RNA

SOCS3:

Suppressor of cytokine signaling 3

TAMs:

Tumor-associated macrophages

TBST:

Tris-buffered saline with Tween-20

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We thank the Department of Pathology, Department of Blood Transfusion, Southwest Hospital, Third Military Medical University, Chongqing, China, for their excellent technical assistance. This work was supported by the National Key Research and Development Program of China (2016YFC1302200) and the National Natural Science Foundation of China (NSFC, No. 81372560).

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Authors and Affiliations

  1. Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People’s Republic of China

    Xiao-Long Fu, Wei Duan, Chong-Yu Su, Pei-Wu Yu & Yong-Liang Zhao

  2. National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, People’s Republic of China

    Fang-Yuan Mao, Yi-Ping Lv, Yong-Sheng Teng & Yuan Zhuang

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  1. Xiao-Long Fu
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Correspondence to Yuan Zhuang or Yong-Liang Zhao.

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Fu, XL., Duan, W., Su, CY. et al. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol Immunother 66, 1597–1608 (2017). https://doi.org/10.1007/s00262-017-2052-5

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  • DOI: https://doi.org/10.1007/s00262-017-2052-5

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