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Gangliosides trigger inflammatory responses via TLR4 in brain glia.

Authors
Jou, I; Lee, JH; Park, SY; Yoon, HJ; Joe, EH; Park, EJ
Citation
The American journal of pathology, 168(5):1619-1630, 2006
Journal Title
The American journal of pathology
ISSN
0002-94401525-2191
Abstract
Gangliosides participate in various cellular events of the central nervous system and have been closely implicated in many neuronal diseases. However, the precise molecular mechanisms underlying the pathological activity of gangliosides are poorly understood. Here we report that toll-like receptor 4 (TLR4) may mediate the ganglioside-triggered inflammation in glia, brain resident immune cells. Gangliosides rapidly altered the cell surface expression of TLR4 in microglia and astrocytes within 3 hours. Using TLR4-specific siRNA and a dominant-negative TLR4 gene, we clearly demonstrate the functional importance of TLR4 in ganglioside-triggered activation of glia. Inhibition of TLR4 expression by TLR4-siRNA suppressed nuclear factor (NF)-kappaB-binding activity, NF-kappaB-dependent luciferase activity, and transcription of inflammatory cytokines after exposure to gangliosides. Transient transfection of dominant-negative TLR4 also attenuated NF-kappaB-binding activity and interleukin-6 promoter activity. In contrast, these activities were slightly elevated in cells with wild-type TLR4. In addition, CD14 was required for ganglioside-triggered activation of glia, and lipid raft formation may be associated with ganglioside-stimulated signal propagation. Taken together, these results suggest that TLR4 may provide an explanation for the pathological ability of gangliosides to cause inflammatory conditions in the brain.
MeSH terms
AnimalsAntigens, CD14/physiologyBrain/cytology*Cells, CulturedCerebral Cortex/cytologyCytokines/geneticsGangliosides/pharmacology*Inflammation/chemically induced*Interleukin-6/geneticsLipopolysaccharides/pharmacologyMembrane Microdomains/physiologyModels, ImmunologicalN-Acetylneuraminic Acid/physiologyNF-kappa B/geneticsNF-kappa B/metabolismNeuroglia/metabolism*Nitric Acid/metabolismNuclear Proteins/metabolismPromoter Regions, GeneticProtein BindingRNA, Small InterferingRatsRats, Sprague-DawleyToll-Like Receptor 4/geneticsToll-Like Receptor 4/metabolism*Transcription, GeneticTransfection
DOI
10.2353/ajpath.2006.050924
PMID
16651628
Appears in Collections:
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
주, 일로조, 은혜박, 은정
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