TY - JOUR
T1 - CXCL10-induced cell death in neurons
T2 - Role of calcium dysregulation
AU - Sui, Yongjun
AU - Stehno-Bittel, Lisa
AU - Li, Shanping
AU - Loganathan, Rajprasad
AU - Dhillon, Navneet K.
AU - Pinson, David
AU - Nath, Avindra
AU - Kolson, Dennis
AU - Narayan, Opendra
AU - Buch, Shilpa
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/2
Y1 - 2006/2
N2 - Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.
AB - Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.
KW - CXCL10
KW - Caspases
KW - Chemokine
KW - HIV-associated dementia
KW - Human
KW - Neuronal apoptosis
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U2 - 10.1111/j.1460-9568.2006.04631.x
DO - 10.1111/j.1460-9568.2006.04631.x
M3 - Article
C2 - 16519660
AN - SCOPUS:33644781577
SN - 0953-816X
VL - 23
SP - 957
EP - 964
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 4
ER -