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  • Title: Lovastatin modulation of microglial activation via suppression of functional CD40 expression.
    Author: Townsend KP, Shytle DR, Bai Y, San N, Zeng J, Freeman M, Mori T, Fernandez F, Morgan D, Sanberg P, Tan J.
    Journal: J Neurosci Res; 2004 Oct 15; 78(2):167-76. PubMed ID: 15378516.
    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.
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