Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia

Abstract

Activated monocytes release a number of substances, including inf lammatory cytokines and eicosanoids, that are highly toxic to cells of the central nervous system. Because monocytic infiltration of the central nervous system closely correlates with HIV-1-associated dementia, it has been suggested that monocyte-derived toxins mediate nervous system damage. In the present study, we show that the HIV-1 transactivator protein Tat significantly increases astrocytic expression and release of monocyte chemoattractant protein-1 (MCP-1). Astrocytic release of ␤-chemokines, which are relatively less selective for monocytes, including RANTES, macrophage inf lammatory protein-1␣, and macrophage inf lammatory protein-1␤, was not observed. We also show that MCP-1 is expressed in the brains of patients with HIV-1-associated dementia and that, of the ␤-chemokines tested, only MCP-1 could be detected in the cerebrospinal f luid of patients with this condition. Together, these data provide a potential link between the presence of HIV-1 in the brain and the monocytic infiltration that may substantially contribute to dementia.

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

“…Astrocytes are an important source of chemokines in the CNS and express CCL2 (Ransohoff et al, 1993;Hayashi et al, 1995;Peterson et al, 1997;Oh et al, 1999) and variably express its cognate receptor CCR2 (Andjelkovic et al, 1999;Dorf et al, 2000), although CCR2 expression among astrocytes is heterogeneous and appears to be regulated by inflammation (Andjelkovic et al, 2002;Croitoru-Lamoury et al, 2003). HIV-1 Tat triggers CCL2 production and inflammatory cascades in astrocytes (Conant et al, 1998). Importantly, opiates enhance CCL2 release by Tat exposed astrocytes , and this results in a significantly increased motility of N9 microglial cells in vitro.…”

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

“…Tat has been shown to induce inflammatory pathways in neurons and glial cells [28][29][30][31] resulted in significant production of numerous cytokines (Table 2) One of the important factors inducing mitochondrial dysfunction is Ca 2+ overload, which primarily occurs during neuroexcitotoxicity [32]. Mitochondria were isolated from rat liver and brain.…”

Prep1/Pbx2 complexes regulate CCL2 expression through the −2578 guanine polymorphism

“…11 We used U87-MG cells in the present studies to examine the molecular basis of the À2578 G phenotype in another relevant astrocytic cell line widely used to study CCL2 expression [20][21][22] and as astrocytes are key producers of CCL2 in the brain, which promotes an influx of monocytes that correlates with HIV/simian immunodeficiency virus (SIV) encephalitis and dementia. 2 We utilized the same 929-bp distal human CCL2 promoter region as the previous study inserted into a pGL4.11 firefly luciferase vector in conjunction with a pGL4.74 renilla luciferase vector in cotransfection experiments to control transfection efficiency. Extracts prepared from transfected U87-MG cells that were either stimulated with IL-1b or left unstimulated for 3 h were subjected to Dual-Luciferase Reporter Assay (Promega Corporation, Madison, WI, USA) to quantitate both firefly and renilla luciferase activity.…”

“…1 Owing to its importance in inflammatory responses, increased levels of CCL2 have been implicated in a variety of disease pathologies including arthersosclerosis, cancer metastisis, multiple sclerosis, Alzheimer's disease and human immunodeficiency virus-associateddementia (HIV-D). [2][3][4][5][6][7] In other settings, CCL2 appears to be beneficial as it protects against initial HIV infection, is neuroprotective against HIV Tat and N-methyl-D-aspartate-induced apoptosis during early HIV infection, and promotes healing following myocardial infarct. [8][9][10] Genetic analysis of the distal CCL2 promoter revealed a polymorphism at À2578 (alternatively designated À2518 11 ) with functional consequences in the context of a luciferase reporter assay.…”