title: Lovastatin modulation of microglial activation via suppression of functional CD40 expression.
abstract: Recent studies have shown that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) possess antiinflammatory and immunomodulatory properties, distinct from their action of lowering serum lipid levels. Moreover, results of epidemiological studies suggest that long-term use of statins is associated with a decreased risk for Alzheimer's disease (AD). Interestingly, lovastatin (one of the most commonly used anticholesterol drugs) treatment of vascular-derived cells has been reported to antagonize activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, and it is well known that the JAK/STAT pathway plays a central role in interferon-gamma (IFN-gamma)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-gamma and amyloid-beta (Abeta) peptide. Moreover, it has been shown that CD40 signaling is critically involved in microglia-related immune responses in the CNS. In this study, we examined the putative role of lovastatin in modulation of CD40 expression and its signaling in cultured microglia. RT-PCR, Western immunoblotting, and flow cytometry data show that lovastatin suppresses IFN-gamma-induced CD40 expression. Additionally, lovastatin markedly inhibits IFN-gamma-induced phosphorylation of JAK/STAT1. Furthermore, lovastatin is able to suppress microglial tumor necrosis factor-alpha, interleukin (IL)-beta1 and IL-6 production promoted either by IFN-gamma or by Abeta peptide challenge in the presence of CD40 cross-linking. To characterize further lovastatin's effect on microglial function, we examined microglial phagocytic capability following CD40 cross-linking. Data reveal that lovastatin markedly attenuates CD40-mediated inhibition of microglial phagocytosis of Abeta. These results provide an insight into the mechanism of the beneficial effects of lovastatin in neurodegenerative disorders, particularly Alzheimer's disease.
authors.affiliation: Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida 33613, USA.
authors.forename: Kirk P
authors.initials: KP
authors.lastname: Townsend
authors.forename: Doug R
authors.initials: DR
authors.lastname: Shytle
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Nan
authors.initials: N
authors.lastname: San
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Melissa
authors.initials: M
authors.lastname: Freeman
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernandez
authors.forename: David
authors.initials: D
authors.lastname: Morgan
authors.forename: Paul
authors.initials: P
authors.lastname: Sanberg
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D010587:Phagocytosis / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; C075222:amyloid beta-protein (1-42); D007371:Interferon-gamma; D008148:Lovastatin; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2