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Macrophage polarization induced by neuropeptide methionine enkephalin (MENK) promotes tumoricidal responses

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Abstract

The aim of this study is to investigate macrophages polarization induced by methionine enkephalin (MENK) that promotes tumoricidal responses in vivo and in vitro. Both phenotypic and functional activities of macrophages were assessed by the quantitative analysis of key surface molecules on macrophages with flow cytometry, immunofluorescent staining, and the production of cytokines with enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction. Our results showed that MENK could down-regulate the expression of CD206 and the production of arginase-1 (the markers of alternatively activated (M2) macrophage) in tumor-associated macrophages in vivo, meanwhile it could significantly up-regulate the expression of CD64, MHC-II, and the production of induced nitric oxide synthase (the markers of classically activated (M1) macrophages). Furthermore, the studies on bone marrow-derived macrophages treated with MENK (10−12 M) in vitro had demonstrated that MENK could markedly increase tumoricidal activity. MENK could also enhance the release of reactive oxidant species and the production of interleukin-12p40, tumor necrosis factor-α, while decrease the production of interleukin-10. In conclusion, MENK could effectively induce M2 macrophages polarizing to M1 macrophages, sequentially to modulate the Th1 responses of the host immune system. Our results suggest that MENK might have great potential as a new therapeutic agent for cancer.

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Abbreviations

MENK:

Methionine enkephalin

OGF:

Opioid growth factor

TAM:

Tumor-associated macrophage

BMDMs:

Bone marrow-derived macrophages

GM-CSF:

Granulocyte macrophage colony stimulating factor

IL-4:

Interleukin-4

IL-12p40:

Interleukin-12p40

IL-10:

Interleukin-10

IFN-γ:

Interferon-γ

TNF-α:

Tumor necrosis factor-α

iNOS:

Induced nitric oxide synthase

Arg-1:

Arginase-1

ROS:

Reactive oxidant species

FCM:

Flow cytometry

RT-PCR:

Reverse transcriptase-polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgments

This work was supported financially by National Natural Science Foundation of China, No. 30771990 (to Fengping Shan) and China Liaoning provincial foundation for international collaboration, No. 2006305007 (to Fengping Shan).

Conflict of interest

The authors declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Science, China Medical University, No. 92, North Second Road, Heping District, Shenyang, 110001, People’s Republic of China

    Wenna Chen, Jinling Liu, Jingjuan Meng, Changlong Lu & Fengping Shan

  2. Center of Teaching and Research, Liaoning University of Traditional Chinese Medicine, No. 79, Chongshan Eastern Road, Huanggu District, Shenyang, 110847, People’s Republic of China

    Wenna Chen & Ximing Li

  3. Institute of Pathology and Pathophysiology, China Medical University, No. 92, North Second Road, Heping District, Shenyang, 110001, People’s Republic of China

    Enhua Wang

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  1. Wenna Chen
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Correspondence to Fengping Shan.

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Chen, W., Liu, J., Meng, J. et al. Macrophage polarization induced by neuropeptide methionine enkephalin (MENK) promotes tumoricidal responses. Cancer Immunol Immunother 61, 1755–1768 (2012). https://doi.org/10.1007/s00262-012-1240-6

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  • DOI: https://doi.org/10.1007/s00262-012-1240-6

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