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* Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and
Precursory Research for Embryonic Science and Technology of Japan Science and Technology Agency, Tokyo, Japan
Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) plays a critical role in inflammatory disorders including experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Although PAF accumulation in the spinal cord (SC) of EAE mice and cerebrospinal fluid of MS patients has been reported, little is known about the metabolic processing of PAF in these diseases. In this study, we demonstrate that the activities of phospholipase A2 (PLA2) and acetyl-CoA:lyso-PAF acetyltransferase (LysoPAFAT) are elevated in the SC of EAE mice on a C57BL/6 genetic background compared with those of naive mice and correlate with disease severity. Correspondingly, levels of groups IVA, IVB, and IVF cytosolic PLA2s, group V secretory PLA2, and LysoPAFAT transcripts are up-regulated in the SC of EAE mice. PAF acetylhydrolase activity is unchanged during the disease course. In addition, we show that LysoPAFAT mRNA and protein are predominantly expressed in microglia. Considering the substrate specificity and involvement of PAF production, group IVA cytosolic PLA2 is likely to be responsible for the increased PLA2 activity. These data suggest that PAF accumulation in the SC of EAE mice is profoundly dependent on the group IVA cytosolic PLA2/LysoPAFAT axis present in the infiltrating macrophages and activated microglia.
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1 This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Science, Culture, Sports and Technology of Japan (to T. S. and S. I.), a grant to the Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan (to S. I.), Grants-in-Aid for Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare, Japan (to S. I.), the Kato Memorial Trust for Nambyo Research (to S. I.), and the Japanese Society for the Promotion of Science (research fellowships to Y.Ki., D.H., and K.Y.). H.S., S.I., and T.S. were supported by the Center for NanoBio Integration (University of Tokyo).
2 Address correspondence and reprint requests to Dr. Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan. E-mail address: tshimizu{at}m.u-tokyo.ac.jp
3 Abbreviations used in this paper: PAF, platelet-activating factor; PLA2, phospholipase A2; LysoPAFAT, acetyl-CoA:lyso-PAF acetyltransferase; LysoPAFAT/LPCAT2, LysoPAFAT/lysophosphatidylcholine acyltransferase 2; lyso-PAF, 1-O-alkyl-sn-glycero-3-phosphocholine; PAFR, PAF receptor; PAF-AH, PAF acetylhydrolase; PC, phosphatidylcholine; iPLA2, calcium-independent PLA2; sPLA2, secretory PLA2; cPLA2, cytosolic PLA2; MS, multiple sclerosis; EAE, experimental allergic encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; SC, spinal cord; ESI-MS/MS, electrospray ionization-tandem mass spectrometry; LPCAT1, lysophosphatidylcholine acyltransferase 1; APMSF, amidinophenylmethanesulfonyl fluoride; GFAP, glial fibrillary acidic protein.
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