期刊
NEUROBIOLOGY OF DISEASE
卷 26, 期 3, 页码 661-670出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2007.03.004
关键词
TNF-alpha; HIV-1; tat; neurotoxicity; macrophages; microglia; U937 cells; THP-1 cells; inflammation
资金
- NCRR NIH HHS [P20 RR017699, P20 RR17699, P20 RR017699-05] Funding Source: Medline
- NIA NIH HHS [P01 AG017628, AG17628] Funding Source: Medline
HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat(1-72) and a mutant Tat(1-72) lacking the neurotoxic epitope (Tat(Delta 31-61)) concentration-dependently and markedly increased TNF-alpha production in macrophage-like differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat, 72 was but Tat(Delta 31-61), was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat(1-72) or Tat(Delta 31,61) were neurotoxic and their immunoneutralization with an anti-TNF-alpha antibody decreased Tat(1-72)- and Tat(Delta 31-61)-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat(1-72) is different from the epitope that is indirectly neurotoxic following production of TNF-a from immune cells, and suggest that therapeutic interventions against TNF-a might be beneficial against HIV-1 associated neurological disorders. (c) 2007 Elsevier Inc. All rights reserved.
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