Abstract
CD38 is a 45-kD ectoenzyme involved in the synthesis of potent calcium (Ca2+)-mobilizing agents, cyclic adenosine diphosphate-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+). In HIV-1-infected patients, increased CD38 expression on CD8+ T cells is linked to immune system activation and progression of HIV-1 infection. However, the role of CD38 upregulation in astrocyte function and HIV-1-associated dementia (HAD-now called HAND: HIV-1-associated neurocognitive disorder) neuropathogenesis is unclear. To these ends, we used interleukin (IL)-1β and HIV-1gp120 to activate primary human astrocytes and measured CD38 expression using real-time polymerase chain reaction and CD38 function by ADP-ribosyl cyclase activity. We also determined cADPR-mediated changes in single-cell intracellular Ca2+ transients in activated astrocytes in presence or absence of ethylene glycol tetraacetic acid. CD38 levels were downregulated using CD38 small-interfering RNA (siRNA) and intracellular Ca2+ concentration ([Ca2+]i) was measured. We previously reported a ∼20-fold rise in CD38 messenger RNA levels in IL-1β-activated astrocytes. We extend this observation and report that HIV-1gp120 potentiated CD38 expression in a dose-dependent manner and also increased CD38 enzyme activity in control and IL-1β-activated astrocytes. We demonstrate higher cADPR levels in IL-1β-activated astrocytes with a corresponding rise in [Ca2+]i upon cADPR application and its non-hydrolysable analog, 3-deaza-cADPR. In activated astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca2+]i to baseline, thus confirming a CD38-cADPR specific response. These data are important for unraveling the mechanisms underlying the role of astrocyte-CD38 in HAD and have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation.
Original language | English (US) |
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Pages (from-to) | 154-164 |
Number of pages | 11 |
Journal | Journal of Neuroimmune Pharmacology |
Volume | 3 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2008 |
Keywords
- Astrocyte
- CD38
- Calcium
- HIV-1-associated dementia
- Neuroinflammation
- cADPR
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Immunology and Allergy
- Immunology
- Pharmacology