TY - JOUR
T1 - Proteasome blockers inhibit TNF-α release by lipopolysaccharide stimulated macrophages and microglia
T2 - Implications for HIV-1 dementia
AU - Fine, Steven M.
AU - Maggirwar, Sanjay B.
AU - Elliott, Paige R.
AU - Epstein, Leon G.
AU - Gelbard, Harris A.
AU - Dewhurst, Stephen
N1 - Funding Information:
We wish to thank Dr. Nancy Rice for the generous gift of anti-c-Rel antibodies and Jodie Dionne for technical assistance. This work was funded in part by National Institutes of Health NIH K08 A101419 (S.M.F.), and NIH P01 MH57556 (L.G.E, H.A.G, S.D.) and The James P. Wilmot Foundation (research fellowship to S.M.F.). The following reagents were obtained through the AIDS Research and Reference Reagent Program, NIAID, NIH: HIV-1 Tat protein from Dr. John Brady, and HIV-1 gp120 CM235 envelope protein and HIV-1 gp120 SF-2 envelope protein from MicroGeneSys, Meriden, CT.
PY - 1999/3/1
Y1 - 1999/3/1
N2 - HIV-1 infection of the central nervous system can cause severe neurologic disease although only microglial cells and brain macrophages are susceptible to productive viral infection. Substances secreted by infected cells are thought to cause disease indirectly. Tumor necrosis factor alpha (TNF-α) is one candidate neurotoxin and is upregulated during HIV-1 infection of the brain, likely via activation of the transcription factor NF- κB. We used the proteasome inhibitors, MG132 and ALLN (N-acetyl-Leu-Leu- Norleucinal), to inhibit NF-κB activation in primary human fetal microgila (PHFM) and primary monocyte derived-macrophages, and showed that they could block TNF-α release stimulated by lipopolysaccharide (LPS) or TNF-α. In addition, we performed electrophoretic mobility shift analysis and determined that in microglia, the p50/p65 heterodimer of NF-κB is activated by LPS stimulation, and is inhibited by MG132. Thus, blockade of NF-κB activation in microglia in vitro can decrease production of TNF-α and may prove to be a novel strategy for treating HIV-1 dementia.
AB - HIV-1 infection of the central nervous system can cause severe neurologic disease although only microglial cells and brain macrophages are susceptible to productive viral infection. Substances secreted by infected cells are thought to cause disease indirectly. Tumor necrosis factor alpha (TNF-α) is one candidate neurotoxin and is upregulated during HIV-1 infection of the brain, likely via activation of the transcription factor NF- κB. We used the proteasome inhibitors, MG132 and ALLN (N-acetyl-Leu-Leu- Norleucinal), to inhibit NF-κB activation in primary human fetal microgila (PHFM) and primary monocyte derived-macrophages, and showed that they could block TNF-α release stimulated by lipopolysaccharide (LPS) or TNF-α. In addition, we performed electrophoretic mobility shift analysis and determined that in microglia, the p50/p65 heterodimer of NF-κB is activated by LPS stimulation, and is inhibited by MG132. Thus, blockade of NF-κB activation in microglia in vitro can decrease production of TNF-α and may prove to be a novel strategy for treating HIV-1 dementia.
KW - Human immunodeficiency virus type 1
KW - Lipopolysaccharide
KW - Macrophage
KW - Microglia
KW - NF-κB
KW - Proteasome inhibitor
KW - Tumor necrosis factor alpha
UR - http://www.scopus.com/inward/record.url?scp=0033104106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033104106&partnerID=8YFLogxK
U2 - 10.1016/S0165-5728(98)00267-7
DO - 10.1016/S0165-5728(98)00267-7
M3 - Article
C2 - 10229115
AN - SCOPUS:0033104106
SN - 0165-5728
VL - 95
SP - 55
EP - 64
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
IS - 1-2
ER -
