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- Title
CXCL10-induced cell death in neurons: role of calcium dysregulation.
- Authors
Sui, Yongjun; Stehno‐Bittel, Lisa; Li, Shanping; Loganathan, Rajprasad; Dhillon, Navneet K.; Pinson, David; Nath, Avindra; Kolson, Dennis; Narayan, Opendra; Buch, Shilpa
- Abstract
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.
- Subjects
CHEMOKINES; INFLAMMATORY mediators; APOPTOSIS; CENTRAL nervous system diseases; NEURODEGENERATION; MULTIPLE sclerosis
- Publication
European Journal of Neuroscience, 2006, Vol 23, Issue 4, p957
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1111/j.1460-9568.2006.04631.x