title: Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13.
abstract: OBJECTIVE
  To address the underlying mechanisms by which curcumin facilitates M2 phenotype polarization of macrophages and its roles in the protective effects during experimental autoimmune myocarditis (EAM).
  
  
  RESULTS
  The expression of classic M2 markers, including macrophage mannose receptor (MMR), arginase-1 (Arg-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ) was upregulated in curcumin-treated Raw264.7 macrophages. Curcumin increased interleukin-4 (IL-4) and interleukin-13 (IL-13) mRNA expression and protein secretion. Curcumin notably increased STAT6 phosphorylation. Leflunomide, a STAT6 inhibitor, and IL-4 and/or IL-13 neutralizing antibodies antagonized the induction of MMR, Arg-1 and PPAR-γ by curcumin in Raw264.7 cells. In vivo, 6-week old male Lewis rats were used to induce EAM and orally administrated with curcumin or corn oil for 3weeks after myosin injection. Cardiac functional parameters, including left ventricular fractional shortening (LVFS), ejection fraction (EF), left ventricular end-systolic diameter (LVEDs) and heart rate (HR) were significantly improved by curcumin treatment. Curcumin also reduced the inflammatory cell infiltration and myocardial mRNA levels of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS). Meanwhile, the myocardial mRNA levels of MMR and Arg-1 were markedly up-regulated by curcumin. Immunofluorescence assay showed that the number of CD68(+) MMR(+) and CD68(+) Arg-1(+) double positive macrophages in curcumin-treated myocardial tissue was significantly higher than untreated control. The number of CD68(+) iNOS(+) double positive macrophages was increased obviously in EAM group, but decreased markedly by curcumin treatment.
  
  
  CONCLUSIONS
  Taken together, these results show that curcumin induces macrophage M2 polarization by secretion of IL-4 and/or IL-13. Curcumin ameliorates EAM by reducing infiltration inflammatory macrophages and by polarizing M0 and M1 macrophages to M2 phenotype.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China; Key Laboratory of Molecular Cardiology Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Medicine, The Second Hospital of Yulin, Yulin 719000, Shaanxi, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China; Key Laboratory of Molecular Cardiology Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Peining
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.affiliation: Department of Nephrology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. Electronic address: imyuewu@gmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China; Key Laboratory of Molecular Cardiology Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Ministry of Education, Xi'an 710061, Shaanxi, China. Electronic address: zuyiyuan@mail.xjtu.edu.cn.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D016764:Cell Polarity; D003474:Curcumin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009205:Myocarditis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D011917:Rats, Inbred Lew; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002316:Cardiotonic Agents; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D003474:Curcumin
keywords: Curcumin; Experimental autoimmune myocarditis; M2 macrophages