Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders.
Neurons express proteins of the classical complement pathway, including C9. Both the mRNA and protein levels for C9 are sharply upregulated in brain areas affected by Alzheimer's disease (AD). Since little is known about the signals that are responsible for this upregulation, we evaluated in human SH-SY5Y neuroblastoma cells the factors which stimulate C9 production. Interferon-gamma, phorbol myristate acetate and interleukin-6 all stimulated C9 mRNA expression but the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, as well as the anaphylatoxin C5a and the bacterial lipopolysaccharide, were ineffective. Immunohistochemical analysis of postmortem human brains for C9 protein demonstrated its presence in many cortical pyramidal neurons in AD, Down's syndrome, the parkinsonism dementia complex of Guam and pallido-ponto-nigral degeneration, as well as in thalamic neurons of progressive supranuclear palsy and ballooned neurons of Pick's disease. Since C9 is required for the membrane attack complex of complement to become functional, interfering with signaling pathways that stimulate its production could offer new therapeutic strategies for treating various neurodegenerative disorders.
Klegeris
A
A
Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
Schwab
C
C
Bissonnette
C J
CJ
McGeer
P L
PL
D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000276:immunology* / Q000473:pathology; D015936:Complement C5a / Q000276:immunology / Q000494:pharmacology; D003186:Complement C9 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000276:immunology*; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
D003186:Complement C9; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate