Exogenous IL-7 induces Fas-mediated human neuronal apoptosis: potential effects during human immunodeficiency virus type 1 infection.
The use of exogenous cytokines is part of translational immune-antiretroviral approaches to induce immune reconstitution and possibly eliminate the persistence of human immunodeficiency virus type 1 (HIV-1) in virally suppressed infected individuals on highly active antiretroviral therapy (HAART). Recently, our laboratories demonstrated that interleukin-7 (IL-7) has significant efficiency in stimulating HIV-1 replication from proviral latency in CD4+ T lymphocytes of infected patients. The authors now investigated the possible role of IL-7 in HIV-1-associated dementia (HAD). The authors demonstrated that the IL-7 receptor is expressed on both human neurons (i.e., differentiated NT2 cells) and human astrocytes, with relatively higher mRNA levels in neurons. The translational protein levels of IL-7 receptor alpha were not proportional to those of the mRNA levels in these central nervous system (CNS)-based cell types. Exogenous IL-7 was observed to only slightly down-regulate IL-7 receptor alpha expression on both neurons and astrocytes, as assayed by Western blotting. Instead of promoting survival, surprisingly, exogenous IL-7 induced neuronal apoptosis, as detected by TUNEL assays. Furthermore, IL-7 augmented neuronal apoptosis induced by HIV-1 gp120. Human apoptosis genomic microarray analyses of IL-7-treated human neurons showed up-regulated expression of proapoptotic genes: protein kinases, caspase-10, FAST kinase, tumor necrosis factor (TNF) receptor, and BCL2-antagonist of cell death. These data suggest that IL-7 leads to neuronal apoptosis by a molecular mechanism(s) that occurs via Fas-mediated activation-induced cell death. These studies may therefore not only be key in evaluating the potential use of IL-7 in vivo as a therapeutic modality, but also suggest that IL-7, which is increased endogenously in HIV-1-infected individuals late in disease, may be involved in the neuronal apoptosis demonstrated during HAD.
Nunnari
Giuseppe
G
Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Giuseppe.Nunnari@jefferson.edu
Xu
Yan
Y
Acheampong
Edward A
EA
Fang
Jianhua
J
Daniel
Rene
R
Zhang
Chune
C
Zhang
Hui
H
Mukhtar
Muhammad
M
Pomerantz
Roger J
RJ
D017209:Apoptosis / Q000276:immunology*; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D023281:Genomics; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D015851:Interleukin-7 / Q000235:genetics*; D008894:Milk Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000276:immunology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020395:Receptors, Interleukin-7 / Q000235:genetics; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015699:HIV Envelope Protein gp120; D015851:Interleukin-7; D008894:Milk Proteins; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019014:fas Receptor; C415350:interleukin-7 receptor, alpha chain