title: Simvastatin reduces CCL2 expression in monocyte-derived cells by induction of a repressive CCL2 chromatin state.
abstract: Statins exert anti-inflammatory characteristics, besides their lipid lowering properties, and may display beneficial effects for the treatment of inflammatory diseases. One possible explanation is that statins interfere in the deregulated gene transcription patterns associated with immune-mediated diseases, although the precise mechanism is not fully understood. Besides gene regulatory proteins, epigenetic mechanisms play an important role in the orchestration of gene expression. Disturbances in the tightly controlled epigenetic mechanisms influence the cellular portrait of expressed genes resulting in the protein dysfunctions found in many inflammatory diseases. In this study, we found that simvastatin reduces secretion and gene expression of CCL2 in monocyte-derived immature dendritic cells and in type 1 macrophages, which is accompanied by increased levels of the 3meK27H3 and 3meK9H3 repressive histone marks and decreased levels of the permissive histone marks AcH3 and 3meK4H3 in CCL2 promoter chromatin. The repressive chromatin status of the CCL2 promoter region affected recruitment of the NF-κB p65 subunit, which controls CCL2 transcription. The down-regulation of CCL2 in these immune cells may therefore impact their chemotactic activity and reduce their recruitment to sites of tissue injury.
authors.affiliation: Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Regional Blood Center of Ribeirão Preto, Center for Cell-based Therapy, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Dalila L
authors.initials: DL
authors.lastname: Zanette
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marja C J A
authors.initials: MC
authors.lastname: van Eggermond
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Haasnoot
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: pjvdelsen@lumc.nl.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects* / Q000235:genetics*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D002843:Chromatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin