Interferon-γ-Induced Neurotoxicity of Human Astrocytes

Activated astrocytes, which can also be referred to as reactive astrocytes or astrogliosis, have been identified in affected regions of common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Activated astrocytes may be beneficial, promoting neuronal survival due to their production of growth factors and neurotrophins. Activated astrocytes can also be detrimental to neighboring neurons in neuroinflammatory processes. Astrocytes exposed to certain inflammatory stimulants in vitro have been shown to release potentially neurotoxic molecules, including inflammatory cytokines, glutamate, nitric oxide and reactive oxygen species. It has recently been shown that adult human astrocytes stimulated with interferon-gamma, a common inflammatory cytokine evidently present in neuropathological brains, exert potent neurotoxicity in vitro. This interferon-gamma-induced astrocytic neurotoxicity is mediated by the activation of the Janus kinase-signal transducer and activator of transcription (STAT) 3 pathway in the astrocytes, and involves intracellular phosphorylation of STAT3 at tyrosine-705 residue. Therefore, control of STAT3 activation in human astrocytes may be a promising new therapeutic strategy for a broad spectrum of neurodegenerative and neuroinflammatory disorders where activated astrocytes may contribute to the pathology.