Adhesive properties and inflammatory potential of citrullinated myelin basic protein peptide 45-89.
Deimination of arginyl residue of myelin basic protein (MBP) reduces cationicity of MBP and impedes the normal myelin membrane assembly. Less ordered structure of MBP is more susceptible to proteolytic attack that may lead to the release of highly immunogenic deiminated peptides into extracellular milieu. We have studied the association of peptides 45-89 derived from citrullinated MBP (C8 isomer) and phosphorylated MBP (C3 isomer) with the myelin lipids in a model membrane system using optical waveguide lightmode spectrometry. The analysis of association/dissociation kinetics to planar lipids under controlled hydrodynamic conditions has shown that MBP 45-89 peptide from citrullinated C8 isomer is less effectively adsorbed on the lipid membrane, than peptide from phosphorylated C3 isomer and packing densities for phosphorylated 45-89 MBP peptide is higher than for citrullinated forms. On the other hand, our results shown that continuous (24 h) exposure of mixed oligodendrocyte/microglial cells to peptides 45-89 from MBP-C8 induces apoptosis via mitochondrial pathway. In addition, peptides 45-89 stimulated the secretion of nitric oxide from microglial cells via induction of iNOS and decreased the level of the inhibitory protein IkB, indicating involvement of the transcription factor NF-kB in these processes. Our results suggest that some citrullinated peptides, initially released from oligodendrocytes, might activate microglia, which produces reactive nitrogen species and generates in turn fatal feedbacks that kill oligodendrocytes.
Ilia State University, 3/5 Cholokhashvili Str, 0162 Tbilisi, Georgia. lali_shanshiashvili@iliauni.edu.ge
Lali V
LV
Shanshiashvili
Irina V
IV
Kalandadze
Jeremy J
JJ
Ramsden
David G
DG
Mikeladze
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000737:chemistry*; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008055:Lipids / Q000737:chemistry; D017628:Microglia / Q000187:drug effects; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013057:Spectrum Analysis
D008055:Lipids; D004676:Myelin Basic Protein; D016328:NF-kappa B; D010446:Peptide Fragments; C041031:myelin basic protein 45-89; D002956:Citrulline; D009569:Nitric Oxide