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Molecular Brain

, 7:85

First Online: 26 November 2014Received: 03 July 2014Accepted: 08 November 2014

Abstract

BackgroundAs the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity.

ResultsWe sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-β, tumour necrosis factor-α, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner.

ConclusionsThe disparity in cholesterol dependence of cytokine release and phagocytosis suggests the two effects occur through distinct molecular mechanisms. These two pathways may provide an opportunity for further refinement of pharmacotherapies for neuroinflammatory, neurodegenerative, and neuropsychiatric disorders.

KeywordsInflammation Cholesterol Mevalonate Phagocytosis AbbreviationsBDNFBrain derived neurotrophic factor

CNSCentral nervous system

DAPI4-,6-diamidino-2-phenylindole

ELISAEnzyme-linked immunosorbant assay

FBSFetal bovine serum

HMG-CoA3-hydroxy-3-methylglutaryl-coenzyme A

Hpβcd2-hydroxypropyl-β-cyclodextrin

HBSSHank’s balanced saline solution

Iba1Ionized Ca-binding protein 1

Il1βInterleukin-1β

JNKc-Jun N-terminal kinase

LPSLipopolysaccharide

mβcdMethyl-β-cyclodextrin

MEVMevalonolactone-mevalonic acid

MHCIIMajor histocompatibility complex II

MTT3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide

NFκBNuclear-factor κB

NHSNormal horse serum

NONitric oxide

PMPlasma membrane

TLR4Toll-like receptor-4

TNFαTumour necrosis factor-α

Electronic supplementary materialThe online version of this article doi:10.1186-s13041-014-0085-7 contains supplementary material, which is available to authorized users.

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Autor: Matthew A Churchward - Kathryn G Todd

Fuente: https://link.springer.com/



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