Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production.
Statins are a group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors which are most effective as lipid lowering agents, and are currently extensively used clinically. Recently, it was also shown that statins affect the immune response. We investigated the effects of lovastatin on the maturation and functional changes of bone marrow-derived dendritic cells (BM-DC). Lovastatin inhibited MHC class II and CD40 expression on DC in a dose-dependent manner, but had lesser effects on CD16, CD80, CD86, and CD11b expression. Nuclear extracts of lovastatin treated DC had decreased NF-kappaB DNA binding activity. Although antigen capture capacity of DC was not affected by lovastatin, the T-cell stimulatory activity of DC was inhibited. Lovastatin up-regulated DC pro-inflammatory cytokine production induced by LPS as measured by intracellular cytokine staining, ELISA and cDNA microarrays. Mevalonate, added in vitro, prevented these effects. These results indicate that lovastatin may inhibit BM-DC maturation and up-regulate cytokine production through a mevalonate dependent pathway, and may cause adverse effects on either innate or adaptive immunity.
Sun
Dongxu
D
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Fernandes
Gabriel
G
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D004247:DNA; D008148:Lovastatin; D008798:Mevalonic Acid