Neurite outgrowth is impaired on HSP70-positive astrocytes through a mechanism that requires NF-κB activation

In the adult central nervous system (CNS), prominent reactive astrocytosis is seen in acute traumatic brain injury, neurodegenerative diseases and a variety of viral infections, Reactive astrocytes synthesize a number of factors that could play different roles in neuronal regeneration. In this study, the effects of thermal stress were evaluated on nuclear factor-kappaB (NF-kappaB) activation and proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) secretion in primary astrocytic cultures. The ability of HSP70-positive astrocytes to support or inhibit neurite outgrowth was investigated in neuron-astrocyte cocultures. Cultured astrocytes from cerebral cortex of rats were exposed to transient hyperthermia (42 degreesC/30 min) and incubated at 37 degreesC for different periods of recovery. During HSP70 accumulation. astrocytes extended large and thick processes associated to rearrangement of glial fibrillary acidic protein (GFAP) filaments and an increase in protein synthesis and GFAP. suggesting an astrogliosis event, A delay of NF-kappaB activation appeared closely related to TNF-alpha secretion by HSP70-positive astrocytes. These cells demonstrated a functional shift from neurite growth-promoting to non-permissive substrate. We also found that gliotoxin, a specific NF-kappaB inhibitor, partially abrogated the inhibitory ability of reactive astrocytes. These findings may suggest a involvement of NF-kappaB and TNF-alpha in modulating the failure of HSP70-positive astrocytes to provide functional support to neuritic outgrowth. (C) 2002 Elsevier Science B.V. All rights reserved.