The use of exogenous cytokines is part of translational immune-antiretroviralapproaches to induce immune reconstitution and possibly eliminate the persistenceof human immunodeficiency virus type 1 (HIV-1) in virally suppressedinfected individuals on highly active antiretroviral therapy (HAART). Recently,our laboratories demonstrated that interleukin-7 (IL-7) has significantefficiency in stimulating HIV-1 replication from proviral latency in CD4+T lymphocytes of infected patients. The authors now investigated the possiblerole of IL-7 in HIV-1–associated dementia (HAD). The authors demonstratedthat the IL-7 receptor is expressed on both human neurons (i.e., differentiatedNT2 cells) and human astrocytes, with relatively higher mRNA levelsin neurons. The translational protein levels of IL-7 receptor α were not proportionalto those of the mRNA levels in these central nervous system (CNS)-based cell types. Exogenous IL-7 was observed to only slightly down-regulateIL-7 receptor α expression on both neurons and astrocytes, as assayed byWestern blotting. Instead of promoting survival, surprisingly, exogenous IL7induced neuronal apoptosis, as detected by TUNEL assays. Furthermore,IL-7 augmented neuronal apoptosis induced by HIV-1 gp120. Human apoptosisgenomic microarray analyses of IL-7–treated human neurons showedup-regulated expression of proapoptotic genes: protein kinases, caspase-10,FAST kinase, tumor necrosis factor (TNF) receptor, and BCL2-antagonist of celldeath. These data suggest that IL-7 leads to neuronal apoptosis by a molecularmechanism(s) that occurs via Fas-mediated activation-induced cell death.These studies may therefore not only be key in evaluating the potential useof IL-7 in vivo as a therapeutic modality, but also suggest that IL-7, whichis increased endogenously in HIV-1–infected individuals late in disease, maybe involved in the neuronal apoptosis demonstrated during HAD.
Exogenous IL-7 induces Fas-mediated human neuronal apoptosis: potential effects during human immunodeficiency virus type 1 infection
NUNNARI GPrimo
;
2005-01-01
Abstract
The use of exogenous cytokines is part of translational immune-antiretroviralapproaches to induce immune reconstitution and possibly eliminate the persistenceof human immunodeficiency virus type 1 (HIV-1) in virally suppressedinfected individuals on highly active antiretroviral therapy (HAART). Recently,our laboratories demonstrated that interleukin-7 (IL-7) has significantefficiency in stimulating HIV-1 replication from proviral latency in CD4+T lymphocytes of infected patients. The authors now investigated the possiblerole of IL-7 in HIV-1–associated dementia (HAD). The authors demonstratedthat the IL-7 receptor is expressed on both human neurons (i.e., differentiatedNT2 cells) and human astrocytes, with relatively higher mRNA levelsin neurons. The translational protein levels of IL-7 receptor α were not proportionalto those of the mRNA levels in these central nervous system (CNS)-based cell types. Exogenous IL-7 was observed to only slightly down-regulateIL-7 receptor α expression on both neurons and astrocytes, as assayed byWestern blotting. Instead of promoting survival, surprisingly, exogenous IL7induced neuronal apoptosis, as detected by TUNEL assays. Furthermore,IL-7 augmented neuronal apoptosis induced by HIV-1 gp120. Human apoptosisgenomic microarray analyses of IL-7–treated human neurons showedup-regulated expression of proapoptotic genes: protein kinases, caspase-10,FAST kinase, tumor necrosis factor (TNF) receptor, and BCL2-antagonist of celldeath. These data suggest that IL-7 leads to neuronal apoptosis by a molecularmechanism(s) that occurs via Fas-mediated activation-induced cell death.These studies may therefore not only be key in evaluating the potential useof IL-7 in vivo as a therapeutic modality, but also suggest that IL-7, whichis increased endogenously in HIV-1–infected individuals late in disease, maybe involved in the neuronal apoptosis demonstrated during HAD.File | Dimensione | Formato | |
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