Abstract
The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-alpha, but not IL-1beta and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-kappaB-dependent mechanisms as well as Tat-induced TNF-alpha production in astrocytes.
Highlights
AIDS dementia complex (ADC) is a neurological disorder associated with HIV infection and affects up to 50% of adult AIDS patients
Vol 41(2), 86-94, 2009 study, we examined the effects of HIV-1 transactivator of transcription (Tat) upon matrix metalloproteinases (MMP)-9 expression in the human astrocyte cell line CRT-MG
CRT-MG cells were exposed to varying doses of HIV-1 Tat (10-1,000 ng/ml) and at 48 h later the culture supernatants were analyzed for expression of MMP-9 by ELISA and Western blot assay
Summary
AIDS dementia complex (ADC) is a neurological disorder associated with HIV infection and affects up to 50% of adult AIDS patients. One of the characteristic features of ADC is the infiltration of monocytes into the CNS which represents one of the early steps to inflammatory events within the CNS (Ozdener, 2005; Rumbaugh and Nath, 2006). HIV-1 Tat mRNA and protein have been detected in the brains of patients with ADC and HIV encephalitis (Wiley et al, 1996; Hudson et al, 2000). This Tat protein, released from the infected cells, has the ability to enter uninfected cells and exert its activity upon the responsive genes (Ensoli et al, 1993)
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