Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappaB (NF-kappaB)-dependent mechanism.
HIV-1 associated dementia is thought to be caused by neuronal damage and death in response to the production of soluble neurotoxic factors by virally infected mononuclear phagocytes. These neurotoxins include HIV-1 Tat. The ability of neurotrophins to promote cell survival prompted us to examine whether neurotrophins might also be capable of opposing the pro-apoptotic effects of Tat. Here, we show that Tat-induced neuronal apoptosis in primary cultures of rat cerebellar granule cells and in neuronally differentiated human SK-N-MC cells is profoundly inhibited by brain-derived neurotrophic factor, nerve growth factor and activity-dependent neurotrophic factor nonamer peptide. These neurotrophins activated the transcription factor NF-kappaB, and inhibition of NF-kappaB activation using a super-repressor IkappaB-alpha mutant was found to block the survival-promoting activity of the neurotrophins. Reporter gene assays and immunoblot experiments revealed that the neurotrophins also up-regulated the expression of Bcl-2, at both the transcriptional and protein levels. Overexpression of the super-repressor IkappaB-alpha mutant prevented this induction of Bcl-2 expression. Moreover, overexpression of either Bcl-2, alone, or the RelA subunit of NF-kappaB, alone, protected neurons from Tat-induced apoptosis. These findings suggest that the activation of NF-kappaB by neurotrophic factors may promote survival of neurons exposed to Tat, via regulation of anti-apoptotic genes including Bcl-2.
Ramirez
S H
SH
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
Sanchez
J F
JF
Dimitri
C A
CA
Gelbard
H A
HA
Dewhurst
S
S
Maggirwar
S B
SB
D015526:AIDS Dementia Complex / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016328:NF-kappa B; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus