title: Anti-inflammatory mechanism of exogenous C2 ceramide in lipopolysaccharide-stimulated microglia.
abstract: Ceramide is a major molecule among the sphingolipid metabolites which are produced in the brain and other organs and act as intracellular second messengers. Although a variety of physiological roles of ceramide have been reported in the periphery and central nervous systems, the role of ceramide in microglial activation has not been clearly demonstrated. In the present study, we examined the effects of exogenous cell permeable short chain ceramides on microglial activation in vitro and in vivo. We found that C2, C6, and C8 ceramide and C8 ceramide-1-phosphate inhibited iNOS and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia. In addition, the administration of C2 ceramide suppressed microglial activation in the brains of LPS-exposed mice. By HPLC and LC/MS/MS analyses, we found that C2 ceramide on its own, rather than its modified form (i.e. ceramide-1-phosphate or long chain ceramides), mainly work by penetrating into microglial cells. Further mechanistic studies by using the most effective C2 ceramide among the short chain ceramides tested, revealed that C2 ceramide exerts anti-inflammatory effects via inhibition of the ROS, MAPKs, PI3K/Akt, and Jak/STAT pathways with upregulation of PKA and hemeoxygenase-1 expressions. Interestingly, we found that C2 ceramide inhibits TLR4 signaling by interfering with LPS and TLR4 interactions. Therefore, our data collectively suggests the therapeutic potential of short chain ceramides such as C2 for neuroinflammatory disorders such as Alzheimer's disease and Parkinson's disease.
authors: Department of Molecular Medicine, Ewha Womans University Medical School, Seoul, Republic of Korea.
authors: Ji-Sun
authors: JS
authors: Jung
authors: Kyong-Oh
authors: KO
authors: Shin
authors: Yong-Moon
authors: YM
authors: Lee
authors: Jin A
authors: JA
authors: Shin
authors: Eun-Mi
authors: EM
authors: Park
authors: Jinju
authors: J
authors: Jeong
authors: Dong-Hyun
authors: DH
authors: Kim
authors: Ji Woong
authors: JW
authors: Choi
authors: Hee-Sun
authors: HS
authors: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D002518:Ceramides; D016207:Cytokines; D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D008156:Luciferases