title: Sublytic terminal complement complexes decrease P0 Gene expression in Schwann cells.
abstract: Complement cascade activation on peripheral nerve myelin can cause myelin destruction. Although terminal complement complexes (TCCs) are transiently detected on Schwann cells (SchCs) during inflammatory neuropathy, SchCs appear resistant to complement-mediated lysis, and little is known about the functional consequences of sublytic TCC deposition on SchCs. We studied the effects of sublytic complement in modulating myelin gene expression at the posttranscriptional and transcriptional levels. Cultured SchCs, stimulated to express protein zero (P0), were treated with sensitizing antibody (Ab) and normal human serum (NHS) complement. P0 mRNA content decreased by 71% during 12 h. In the presence of actinomycin D, P0 mRNA levels declined 50% following incubation with Ab plus 10% NHS over 6 h, compared with control levels, suggesting enhanced P0 mRNA degradation. The decreases, in part, reflected TCC formation because C7 reconstitution of Ab plus C7-depleted human serum (C7dHS) or TCCs assembled from purified components down-regulated P0 mRNA 53 and 55% over that of Ab plus C7dHS or heat-activated components, respectively. Expression of a P0 promoter/luciferase reporter construct transiently transfected into SchCs was reduced 70% by sublytic TCCs at 6 h, demonstrating that P0 gene transcription was also inhibited. c-jun mRNA was up-regulated within 30 min by sublytic TCCs, before the reduction in P0 mRNA expression. Our data suggest that sublytic complement activation on SchCs may contribute to peripheral nerve demyelination by decreasing expression of genes important in myelin formation and compaction.
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Dashiell
authors.forename: C L
authors.initials: CL
authors.lastname: Koski
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D003167:Complement Activation; D003184:Complement C7 / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000494:pharmacology*; D018076:DNA, Complementary / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun; D006801:Humans; D018993:Myelin P0 Protein / Q000096:biosynthesis / Q000235:genetics*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D050816:Octamer Transcription Factor-6; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D012584:Sciatic Nerve; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D003184:Complement C7; D015938:Complement Membrane Attack Complex; D018076:DNA, Complementary; D018993:Myelin P0 Protein; D019384:Nucleic Acid Synthesis Inhibitors; C494178:POU3F1 protein, human; C494179:Pou3f1 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D050816:Octamer Transcription Factor-6; D003609:Dactinomycin