Exposure of Astrocytes to Hypoxia/Reoxygenation Enhances Expression of Glucose‐Regulated Protein 78 Facilitating Astrocyte Release of the Neuroprotective Cytokine Interleukin 6

Astrocytes exposed to hypoxia (H) or hypoxia/reoxygenation (H/R) maintain cell viability and display changes in protein biosynthesis. Sodium dodecyl sulfate‐polyacrylamide gel electrophoresis of metabolically labeled astrocytes exposed to H showed induction of an ≈78‐kDa polypeptide that demonstrated sequence identity with glucose‐regulated protein (GRP) 78. Cell lysates from H/R astrocytes displayed induction of neuroprotective interleukin (IL) 6, which was present in a high‐molecular‐weight complex also containing GRP78, suggesting that GRP78 might be functioning as a chaperone during cellular stress consequent on H/R. Introduction of anti‐sense oligonucleotide to GRP78 into astrocytes prevented expression of the protein and suppressed H/R‐induced astrocyte release of IL‐6 by ≈50%. These data indicate that modulation of astrocyte properties during oxygen deprivation results, in part, from intracellular glucose depletion and subsequent expression of GRP78, which sustains generation of neuroprotective IL‐6 under the stress of H/R.