title: The p38 MAPK NF-κB pathway, not the ERK pathway, is involved in exogenous HIV-1 Tat-induced apoptotic cell death in retinal pigment epithelial cells.
abstract: The mechanism through which human immunodeficiency virus (HIV) infection causes retinal disease and the loss of vision in AIDS patients remains unknown. The HIV-1 transactivator protein Tat (HIV-1 Tat) plays a pivotal role in the pathogenesis of HIV-1 infection and is often described as pleiotropic at different concentrations. In a previous study, we demonstrated that the HIV-1 Tat protein can disrupt the barrier function of retinal pigment epithelium (RPE) at 100 nM without affecting cell viability. The present study was undertaken to determine if HIV-1 Tat can induce RPE cell death at different concentrations and to determine the mechanism of any observed cell death. The results demonstrated that two RPE cell lines (ARPE-19 and D407) treated with Tat at concentrations of 200 nM and above exhibited reduced growth and apoptosis in a dose- and time-dependent manner. The disruption of mitochondrial outer membrane permeabilisation, the activation of caspase-3/7 and 9, the downregulation of Bcl-2, the upregulation of Bax, and the activation of p38 MAPK, ERK and NF-κB were all observed in HIV-1 Tat-treated RPE cells. When exposed to an inhibitor or transfected with siRNA of p38 MAPK and NF-κB, the level of cell death and deregulation of the expression of the apoptotic protein were attenuated. These effects were not observed with an ERK inhibitor or siRNA. Based on these results, we suggest that the induction of apoptosis by HIV-1 Tat in RPE cells may be mediated by p38 MAPK and NF-κB activation and involve the mitochondrial pathway. Therefore, these pathways may provide clues leading to novel therapeutic approaches for the retinopathy induced by HIV infection.
authors.affiliation: Department of Ophthalmology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Bai
authors.forename: Xiuping
authors.initials: X
authors.lastname: Zhu
authors.forename: Ting
authors.initials: T
authors.lastname: Ma
authors.forename: Jianming
authors.initials: J
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015497:HIV-1 / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051028:bcl-2-Associated X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053179:Caspase 7
keywords: Apoptosis; HIV-1 Tat; NF-κB; Retinal pigment epithelial; p38 MAPK