title: Statins inhibit iNOS-mediated microbicidal potential of activated monocyte-derived dendritic cells by an IFN-β-dependent mechanism.
abstract: Statins are prescribed to 25 million people worldwide for treating hypercholesterolemia and reducing the risk of cardiovascular diseases. However, the side effects of statins on immunity, and particularly on DC immunobiology, have not been analyzed in-depth. Here, we have investigated the impact of lovastatin treatment during monocyte differentiation into DCs on the responsiveness of the resulting monocyte-derived DCs (moDCs) to TLR-mediated activation. Lovastatin positively regulated TLR4 signaling in LPS-stimulated moDCs, leading to strong activation of p38 MAP-kinase paralleled by increased proinflammatory cytokine and IFN-β production. In contrast, lovastatin promoted negative regulation of IFN-β-mediated autocrine signaling through the IFN-αβ receptor, paralleled by low expression of the transcription factor IRF-1, leading to the inhibition of the enzymes iNOS and HO-1. Defective activation of iNOS/HO-1 resulted in limited cytoprotective capacity against ROS and reduced microbicidal potential. These data were validated using an in vivo model of Listeria monocytogenes infection, which revealed that iNOS activation by splenic inflammatory moDCs, specialized in NO and TNF-α production, was strongly reduced in lovastatin-treated, Listeria-infected mice. Statin treatment could have severe implications in immunity against pathogens due to defective iNOS/HO-1 metabolism activation in inflammatory moDCs that might lead to immune failure.
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: Pilar M
authors.initials: PM
authors.lastname: Domínguez
authors.forename: María
authors.initials: M
authors.lastname: López-Bravo
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Carlos
authors.initials: C
authors.lastname: Ardavín
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D016899:Interferon-beta / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D008148:Lovastatin / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016899:Interferon-beta; D008148:Lovastatin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse