Curcumin mediated epigenetic modulation inhibits TREM-1 expression in response to lipopolysaccharide.
Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the immunoglobulin superfamily expressed on macrophage and neutrophils and is emerging as a potent amplifier of TLR initiated inflammatory responses. Blockade of TREM-1 improves survival in animal models of sepsis. In this study, we show that curcumin or diferuloylmethane, a yellow pigment present in turmeric, a major ingredient of curry spice inhibited the expression of TREM-1 in vitro in primary bone marrow derived macrophages and in vivo in lungs of mice with sepsis. Chromatin immunoprecipitation assay confirmed that curcumin inhibits the binding of p65 to TREM-1 promoter in response to LPS. Further we show that curcumin inhibited p300 activity in the TREM-1 promoter region leading to hypoacetylation of histone 3 and 4 in the lysine residues. Inhibition of TREM-1 by curcumin is oxidant independent. These studies are the first report to define a detailed molecular mechanism by which curcumin exerts anti-inflammatory effects through regulation of TREM-1 gene activity and provide additional mechanistic insights into the anti-inflammatory effect of curcumin.
Department of Veterans Affairs, Jesse Brown VA Hospital, University of Illinois, Chicago, IL, United States.
Zhihong
Z
Yuan
Mansoor Ali
MA
Syed
Dipti
D
Panchal
Daniel
D
Rogers
Myungsoo
M
Joo
Ruxana T
RT
Sadikot
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D003474:Curcumin / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1; D000099224:p300-CBP-Associated Factor
D003474:Curcumin; D006657:Histones; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D050880:p300-CBP Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; D000099224:p300-CBP-Associated Factor; C517262:TREM1 protein, mouse