title: Methionine enkephalin (MENK) mounts antitumor effect via regulating dendritic cells (DCs).
abstract: MENK, an endogenous opioid peptide has been reported to have many immunological and antitumor activities. So far the detailed mechanisms of antitumor through regulating DCs by MENK have not been elucidated yet. The aim of this work was to investigate the antitumor mechanisms of MENK via regulating DC. The monitoring methods, such as ELISA, MTS assay, CFSE, Real-time PCR and Western blot were included in our research. We found bone marrow derived dendritic cells (BMDCs) in 36 female C57BL/6 mice treated with MENK enhanced expression of key surface molecules, increased production of critical cytokines reduced endocytosis of FITC-dextran, upregulated TLR4 through MyD88/NF-κB signaling pathway and mounted higher antitumor activity. These observations were further supported by an enhancement of nuclear translocation of the p65NF-κB subunit involved in this process. Surprisingly, mu-opioid receptors were the main participants of this kind of activation, not delta-opioid receptors nor kappa-opioid receptors, and these interactions could be partly blocked by Naltrexone (a kind of opioid antagonist). In vivo study the activated CD4+, CD8+T cells and decreased ability to induce differentiation of Foxp3+regulatory T cells were detected post treatment of MENK. Thus, it is concluded that MENK could exert antitumor effect through precisely regulating opioid receptor mediated functions of DCs. In addition, MENK treated DCs may serve as a new immunotherapy approach against tumor.
authors.affiliation: Department of Immunology, School of Basic Medical Science, China Medical University, No. 77, Puhe Road, Shenyang 110122, China; Center of Biological Therapy, Cancer Hospital of China Medical University, No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Dermatology, No. 1 Hospital, China Medical University, No. 92, North Second Road, Shenyang 110001, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Gao
authors.affiliation: Center of Teaching & Research, Liaoning University of Traditional Chinese Medicine, No. 79, Chongshan Eastern Road, Shenyang 110847, China.
authors.forename: Wenna
authors.initials: W
authors.lastname: Chen
authors.affiliation: Immune Therapeutics, Inc., 37 North Orange Avenue, Suite 607, Orlando, FL 32801, USA.
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Plotnikoff
authors.affiliation: Immune Therapeutics, Inc., 37 North Orange Avenue, Suite 607, Orlando, FL 32801, USA.
authors.forename: Noreen
authors.initials: N
authors.lastname: Griffin
authors.affiliation: Center of Biological Therapy, Cancer Hospital of China Medical University, No. 44, Xiaoheyan Road, Shenyang 110042, Liaoning Province, China.
authors.forename: Guirong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medical Science, China Medical University, No. 77, Puhe Road, Shenyang 110122, China. Electronic address: fpshan@cmu.edu.cn.
authors.forename: Fengping
authors.initials: F
authors.lastname: Shan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004744:Enkephalin, Methionine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D016328:NF-kappa B; D004744:Enkephalin, Methionine
keywords: Antitumor; Bone marrow-derived dendritic cells (BMDCs); Immunoregulation; Methionine enkephalin (MENK); Opioid receptor