Background:  Using exogenous cytokines, such as interleukin-2 (IL-2), is an immune-antiretroviral approach to induce immune reconstitution and possibly eliminate the persistence of HIV-1 in virally suppressed infected individuals on HAART. Recently, our labs demonstrated that interleukin-7 (IL-7) has greater efficiency than IL-2 in stimulating HIV-1 replication. We then further investigated the role of IL-7 on the central nervous system for potential treatment of HIV-1-associated dementia (HAD).

Methods:  We subjected differentiated NT-2 neuron cultures to TUNEL apoptosis assays, semi-quantification RT-PCR, Western blotting, and gene microarray analyses.

Results:  We observed that IL-7 receptors are expressed on both human neurons and astrocytes, with higher mRNA levels in neurons. The translational levels of IL-7 receptor-a were not proportional to those of transcriptional levels. Exogenous IL-7 up-regulated IL-7 receptor-a expression on neurons, whereas it down-modulated IL-7 receptor on astrocytes. Instead of promoting survival, surprisingly, exogenous IL-7 induced potent neuronal apoptosis detected by TUNEL assays. The janus activated kinase 3/signal transducer and activator of transcription 5 receptors were up-regulated on astrocytes, whereas they were down-regulated on neurons by IL-7. Gene microarray analyses showed the up-regulated expression of pro-apoptotic genes:  FAST kinase, TNF receptor, BCL2-antagonist of cell death, caspase-10, growth arrest, and DNA-damage-inducible alpha.

Conclusions:  Our data suggest, in contrast to the potential positive roles of IL-7 in immune-antiretroviral HIV-1 therapy, that IL-7 could cause neuronal programmed cell death via Fas and TNF pathways, both during therapy and via endogenous secretion during AIDS.

Keywords: IL7; Neurons; Apoptosis