title: Curcumin enhances non-opsonic phagocytosis of Plasmodium falciparum through up-regulation of CD36 surface expression on monocytes/macrophages.
abstract: OBJECTIVE
  Curcumin is a natural plant product with antimalarial activity and immunomodulatory properties. In this study we aimed to investigate its effects on CD36 expression and CD36-mediated Plasmodium falciparum phagocytosis as well as the role played by reactive oxygen species (ROS) and the peroxisome proliferator-activated receptor γ retinoid X receptor (PPARγ-RXR) in these processes.
  
  
  METHODS
  In vitro antimalarial activity was evaluated by the [³H]hypoxanthine assay. ROS production and surface CD36 in human monocyte/macrophages were measured by flow cytometry. PPARγ and CD36 mRNA expression was determined by the QuantiGene Plex® assay and RT-qPCR. Nuclear PPARγ activation was analysed by a DNA-binding ELISA while nuclear erythroid-related factor 2 (Nrf2) expression was analysed by western blotting. P. falciparum phagocytosis was assessed by light microscopy.
  
  
  RESULTS
  Curcumin's antimalarial activity was confirmed and did not differ between drug-susceptible and -resistant P. falciparum strains. Curcumin increased monocyte ROS production and expression of PPARγ and CD36 at the mRNA and protein levels. Although PPARγ activation was blocked by the PPARγ antagonist GW9662, CD36 expression and CD36-mediated P. falciparum phagocytosis were only inhibited by N-acetylcysteine (NAC), suggesting a PPARγ-independent CD36 expression pathway. We then identified seven putative Nrf2 antioxidant response elements on the CD36 gene promoter and showed that NAC inhibited curcumin-induced Nrf2 protein expression.
  
  
  CONCLUSIONS
  CD36 expression and CD36-mediated P. falciparum phagocytosis by curcumin are dependent on ROS production and probably involve the Nrf2 pathway. The dual immunomodulatory and antimalarial mechanisms of curcumin action may mean that curcumin has potential as an adjuvant treatment limiting the risk of recrudescence following standard antimalarial therapy.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine-LSHTM, Keppel Street, London WC1E 7HT, UK.
authors.forename: Patrice N
authors.initials: PN
authors.lastname: Mimche
authors.forename: Eloise
authors.initials: E
authors.lastname: Thompson
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
mesh_terms: D018955:CD36 Antigens / Q000096:biosynthesis*; D003474:Curcumin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008853:Microscopy; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis; D047495:PPAR gamma / Q000096:biosynthesis; D010587:Phagocytosis / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D007155:Immunologic Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D003474:Curcumin