Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor.
Programmed cell death contributes to the morbidity and mortality of several neurological disorders including stroke, Alzheimer's disease and human immunodeficiency virus (HIV)-associated dementia. Patients with HIV dementia show evidence of programmed cell death in brain. In vitro data demonstrates several neurotoxic products of macrophage infection that cause neural cell death, including tumor necrosis factor alpha (TNFalpha) and platelet activating factor (PAF). We treated human brain aggregate cultures with these cytokines and determined their effect on the mRNA and protein levels for Bcl-2, Bcl(x) and Bax alpha. TNFalpha and PAF differentially regulate the Bcl-2 family of proteins at a post-transcriptional level. Following TNFalpha treatment, Bcl-2 protein is significantly decreased, and at least one additional Bax isomer emerges. Bcl(xL) protein is slightly increased after treatment with either cytokine. We demonstrated that overexpression of Bcl-2 in brain aggregate cultures protects cells from TNFalpha-induced damage but has no effect on cell damage induced by PAF. We conclude that Bcl-2 and Bax alpha proteins play significant roles in modulating neural cell death from TNFalpha- but not from PAF-induced cell damage.
Pulliam
L
L
Department of Laboratory Medicine, University of California, San Francisco, Veterans Affairs Medical Center, USA.
Zhou
M
M
Stubblebine
M
M
Bitler
C M
CM
D015526:AIDS Dementia Complex / Q000473:pathology / Q000628:therapy; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005786:Gene Expression Regulation; D006801:Humans; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D010972:Platelet Activating Factor; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein