title: Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor.
abstract: Epidemiological studies show reduced risk of Alzheimer's disease (AD) among patients using non-steroidal inflammatory drugs (NSAID) indicating the role of inflammation in AD. Studies have shown a chronic CNS inflammatory response associated with increased accumulation of amyloid peptide and activated microglia in AD. Our previous studies showed that interaction of Abeta1-40 or fibrilar Abeta1-42 caused activation of nuclear transcription factor, early growth response-1 (Egr-1), which resulted in increased expression of cytokines (TNF-alpha and IL-1beta) and chemokines (MIP-1beta, MCP-1 and IL-8) in monocytes. We determined whether curcumin, a natural product known to have anti-inflammatory properties, suppressed Egr-1 activation and concomitant expression of cytochemokines. We show that curcumin (12.5-25 microm) suppresses the activation of Egr-1 DNA-binding activity in THP-1 monocytic cells. Curcumin abrogated Abeta1-40-induced expression of cytokines (TNF-alpha and IL-1beta) and chemokines (MIP-1beta, MCP-1 and IL-8) in both peripheral blood monocytes and THP-1 cells. We found that curcumin inhibited Abeta1-40-induced MAP kinase activation and the phosphorylation of ERK-1/2 and its downstream target Elk-1. We observed that curcumin inhibited Abeta1-40-induced expression of CCR5 but not of CCR2b in THP-1 cells. This involved abrogation of Egr-1 DNA binding in the promoter of CCR5 by curcumin as determined by: (i) electrophoretic mobility shift assay, (ii) transfection studies with truncated CCR5 gene promoter constructs, and (iii) chromatin immunoprecipitation analysis. Finally, curcumin inhibited chemotaxis of THP-1 monocytes in response to chemoattractant. The inhibition of Egr-1 by curcumin may represent a potential therapeutic approach to ameliorate the inflammation and progression of AD.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Ranjit K
authors.initials: RK
authors.lastname: Giri
authors.forename: Vikram
authors.initials: V
authors.lastname: Rajagopal
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kalra
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D002843:Chromatin / Q000378:metabolism; D030024:Curcuma / Q000737:chemistry*; D003474:Curcumin / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051766:Early Growth Response Protein 1; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D002843:Chromatin; D016207:Cytokines; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D010446:Peptide Fragments; D012333:RNA, Messenger; D019713:Receptors, CCR5; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003474:Curcumin