Platelet-activating factor production in the spinal cord of experimental allergic encephalomyelitis mice via the group IVA cytosolic phospholipase A2-lyso-PAFAT axis.
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 A(2) (PLA(2)) 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 PLA(2)s, group V secretory PLA(2), 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 PLA(2) is likely to be responsible for the increased PLA(2) activity. These data suggest that PAF accumulation in the SC of EAE mice is profoundly dependent on the group IVA cytosolic PLA(2)/LysoPAFAT axis present in the infiltrating macrophages and activated microglia.
Kihara
Yasuyuki
Y
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Yanagida
Keisuke
K
Masago
Kayo
K
Kita
Yoshihiro
Y
Hishikawa
Daisuke
D
Shindou
Hideo
H
Ishii
Satoshi
S
Shimizu
Takao
T
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003600:Cytosol / Q000201:enzymology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000633:toxicity; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000633:toxicity; D010972:Platelet Activating Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation / Q000276:immunology
D006023:Glycoproteins; D018836:Inflammation Mediators; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010972:Platelet Activating Factor; C445081:myelin oligodendrocyte glycoprotein (35-55); D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse; D054513:Group IV Phospholipases A2