Pro-inflammatory cytokine; tumor-necrosis factor-alpha (TNF-α) inhibits astrocytic support of neuronal survival and neurites outgrowth

Abstract

Reactive astrogliosis has been implicated in the failure of axonal regeneration in adult mammalian Central Nervous System (CNS).\rIt is our hypothesis that inflammatory cytokines act upon astrocytes to alter\rtheir biochemical and physical properties, which may in turn be responsible for\rthe failure of neuronal regeneration. We have therefore examined the effect\rof tumor-necrosis factor-alpha (TNF-α) on the ability of astrocytes to support the\rsurvival of the cortical neurons and the growth of the neurites. Mouse astrocytes\rand cortical neuronal cultures were prepared. It was observed that when neurons\rwere cultured in absence of astrocytes only a few of them grew and survived\ronly for 5-6 days. These neurons had small cell bodies and few, short\rneurites. However, when the same numbers of neurons were cultured on the top of\rastrocytes, more neurons grew and survived up to 16-18 days. They had\rbigger cell bodies and many long branched neurites that formed anestamosing networks. The neurons then coalesced and the neurites formed thick bundles. When\rthe same numbers of neurons were grown on the top of astrocytes pre-treated\rwith TNF-α,\rfew neurons survived up to 13 days. The neurites of the survived neurons were\rshorter than neurites of neurons grown on normal astrocytes and did not form\rbundles. In addition, TNF-α stimulated the expression of glial fibrillary acidic protein (GFAP) by\rastrocytes. These results support that the pro-inflammatory cytokine, TNF-α modulates the gliosis and that the\rastrocytic cell supports neuronal survival and neurite outgrowth.