Enhanced degradation of messenger RNA encoding myelin proteins by terminal complement complexes in oligodendrocytes.
Sublytic terminal C complexes (TCC) are capable of stimulating cells and affect the target cell activity. Activation of TCC that generates leukotriene B4 in oligodendrocytes, the myelin-forming cells of the central nervous system, is also a required process in antibody-mediated demyelination of rodent cerebellar explants. In the present study, the effect of TCC on myelin protein gene expression was studied in primary rat oligodendrocytes in culture. Sublytic activation of serum C reduced accumulation of mRNA encoding proteolipid protein (PLP) and myelin basic protein (MBP) within 1 h, but not beta-actin mRNA. C activation, on the other hand, induced sustained expression of c-jun mRNA. Experiments using C7-deficient human serum to determine the role of TCC showed that selective MBP and PLP mRNA down-regulation was achieved only when C7 was reconstituted to form TCC. The C7 requirement was also observed in the presence of alpha-amanitin. Post-transcriptional regulation was explored by determining mRNA decay, which demonstrated that the MBP and PLP mRNA were selectively destabilized when C7 was reconstituted. Limited exploration of the signals responsible for the TCC effect revealed that down-regulation of mRNA by TCC was significantly influenced by Ca2+ on PLP, whereas MBP did not show the same Ca2+ sensitivity as PLP. The TCC-mediated MBP mRNA decay was completely abrogated by HA1004, an inhibitor for the cAMP- and cGMP-dependent protein kinases, but not by H7, a protein kinase C inhibitor.
Shirazi
Y
Y
Department of Pathology, University of Maryland School of Medicine, Baltimore 21201.
Rus
H G
HG
Macklin
W B
WB
Shin
M L
ML
D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D016758:Genes, jun; D066298:In Vitro Techniques; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009836:Oligodendroglia / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000546:Amanitins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger; D003165:Complement System Proteins; D011494:Protein Kinases; D002118:Calcium