ABSTRACT
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.
Subject(s)
Brain/immunology , Complement C9/genetics , Gene Expression Regulation , Neurodegenerative Diseases/immunology , Neurons/immunology , RNA, Messenger , Aged , Aged, 80 and over , Brain/pathology , Complement C5a/immunology , Complement C5a/pharmacology , Complement C9/analysis , Complement C9/immunology , Female , Humans , Interferon-gamma/immunology , Interferon-gamma/pharmacology , Interleukin-1/immunology , Interleukin-1/pharmacology , Interleukin-6/immunology , Interleukin-6/pharmacology , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Male , Middle Aged , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Neurons/cytology , Tetradecanoylphorbol Acetate/pharmacology , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
This study evaluated complement mRNA expression in human brain microvessel endothelial cells (HBMEC), human umbilical vein endothelial cells (HUVEC), and cells of the human derived ECV304 line. Cerebral endothelial cells and HUVEC expressed detectable levels of complement gene mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C7, C8 gamma-subunit and C9. In addition to C6 mRNA, C1q and C9 were not detected in ECV304 cells. These results indicate that endothelial cells may be a source of complement proteins in brain and other organs of the body.
