HYPOXIA REOXYGENATION-MEDIATED INDUCTION OF ASTROCYTE INTERLEUKIN-6 -A PARACRINE MECHANISM POTENTIALLY ENHANCING NEURON SURVIVAL/

To elucidate mechanisms underlying neuroprotective properties of astro cytes in brain ischemia, production of neurotrophic mediators was stud ied in astrocytes exposed to hypoxia/reoxygenation (H/R). Rat astrocyt es subjected to H/R released increased amounts of interleukin (IL) 6 i n a time-dependent manner, whereas levels of tumor necrosis factor and IL-1 remained undetectable. IL-6 transcripts were induced in hypoxia and the early phase of reoxygenation, whereas synthesis and release of IL-6 antigen/activity occurred during reoxygenation. Elevated levels of IL-6 mRNA were due, at least in part, to increased transcription, a s shown by nuclear runoff analysis. The mechanism stimulating synthesi s and release of IL-6 antigen by astrocytes was probably production of reactive oxygen intermediates (ROIs), which occurred within 15-20 min utes after placing hypoxia cultures back into normoxia, as the inhibit or diphenyl iodonium inhibited the burst of ROIs and subsequent IL-6 g eneration (blockade of nitric oxide formation had no effect on ROI gen eration or IL-6 production). Enhanced IL-6 generation was also observe d in human astrocytoma cultures exposed to H/R. Survival of differenti ated PC12 cells exposed to H/R was potentiated by conditioned medium f rom H/R astrocytes, an effect blocked by neutralizing anti-IL-6 antibo dy. In a gerbil model of brain ischemia, IL-6 activity was lower in th e hippocampus, an area sensitive to ischemia, compared with IL-6 activ ity in the cortex, an area more resistant to ischemia. IL-6 antigen, d emonstrated immunohistochemically, was increased in astrocytes from is chemic regions of gerbil brain. These data suggest that H/R enhances t ranscription of IL-6, resulting in increased translation and release o f IL-6 antigen after the burst of ROI generated early during reoxygena tion. Release of IL-6 from astrocytes could exert a paracrine neurotro phic effect in brain ischemia.