title: Gangliosides trigger inflammatory responses via TLR4 in brain glia.
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.
authors.affiliation: Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 443-721, Korea.
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Park
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000235:genetics; D005732:Gangliosides / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced*; D015850:Interleukin-6 / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D021962:Membrane Microdomains / Q000502:physiology; D018448:Models, Immunological; D019158:N-Acetylneuraminic Acid / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D017942:Nitric Acid / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D016207:Cytokines; D005732:Gangliosides; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D017942:Nitric Acid; D019158:N-Acetylneuraminic Acid