期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 14, 期 11, 页码 1793-1799出版社
BLACKWELL PUBLISHING LTD
DOI: 10.1046/j.0953-816x.2001.01808.x
关键词
cell culture; HIV-1 associated encephalopathy; human glioblastoma cells; rat; TNF alpha
The trans-activator protein Tat of the human immunodeficiency virus type 1 (HIV-1) is regarded as an injurious molecule in the pathogenesis of HIV-1 associated encephalopathy (HIVE). We investigated the effects of Tat on neuroligand-induced intracellular Ca2+ increase in cultured astroglial cells. Rat cortical astrocytes, human glioblastoma cells and glial restricted precursor cells, from a human embryonic teratocarcinoma cell line, were incubated with recombinant Tat (100 ng/mL for 60 min) which induced a significant reduction of glutamate or ATP-induced intracellular Ca2+ increase ('glutamate response', 'ATP response'). The reduction of the glutamate response was also observed following cell incubation with cell extracts of HeLa-T4(+) cells transiently transfected with an expression plasmid coding for Tat. However, inactivation of the transcriptional trans-activity of Tat, by using a mutant form of Tat, as well as inhibition of de novo protein synthesis by cycloheximide abolished the effect on the glutamate response. This suggests that Tat acts upon induction of a so far unknown cellular gene whoes gene product causes the reduction of glutamate responses. As the effect of Tat resembles the effect of TNF alpha on glutamate responses [Koller et al. (2001) Brain Res., 893, 237-243] which is locally released within the brains of HIVE patients, we also tested for synergistic effects of Tat and TNF alpha on the glutamate response. Low concentrations of Tat in combination with subthreshold concentrations of TNF alpha also elicited a marked reduction of astroglial glutamate responses. Our data suggest that Tat and TNF alpha, both by itself and synergistically, induce astroglial dysfunction.
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