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

Cancer Immunol Immunother. 2012 Oct;61(10):1755-68. doi: 10.1007/s00262-012-1240-6. Epub 2012 Mar 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / biosynthesis
  • Cell Line, Tumor
  • Cell Polarity / drug effects*
  • Cytokines / biosynthesis
  • Cytokines / metabolism
  • Down-Regulation / drug effects
  • Enkephalin, Methionine / therapeutic use*
  • Histocompatibility Antigens Class II / biosynthesis
  • Lectins, C-Type / biosynthesis
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Male
  • Mannose-Binding Lectins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Nitric Oxide Synthase Type II / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Receptors, Cell Surface / biosynthesis
  • Receptors, IgG / biosynthesis
  • Up-Regulation


  • Cytokines
  • Histocompatibility Antigens Class II
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Reactive Oxygen Species
  • Receptors, Cell Surface
  • Receptors, IgG
  • mannose receptor
  • Enkephalin, Methionine
  • Nitric Oxide Synthase Type II
  • Arg1 protein, mouse
  • Arginase