Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival.
To elucidate mechanisms underlying neuroprotective properties of astrocytes in brain ischemia, production of neurotrophic mediators was studied in astrocytes exposed to hypoxia/reoxygenation (H/R). Rat astrocytes subjected to H/R released increased amounts of interleukin (IL) 6 in 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, as shown by nuclear runoff analysis. The mechanism stimulating synthesis and release of IL-6 antigen by astrocytes was probably production of reactive oxygen intermediates (ROIs), which occurred within 15-20 minutes after placing hypoxia cultures back into normoxia, as the inhibitor diphenyl iodonium inhibited the burst of ROIs and subsequent IL-6 generation (blockade of nitric oxide formation had no effect on ROI generation or IL-6 production). Enhanced IL-6 generation was also observed in human astrocytoma cultures exposed to H/R. Survival of differentiated PC12 cells exposed to H/R was potentiated by conditioned medium from H/R astrocytes, an effect blocked by neutralizing anti-IL-6 antibody. In a gerbil model of brain ischemia, IL-6 activity was lower in the hippocampus, an area sensitive to ischemia, compared with IL-6 activity in the cortex, an area more resistant to ischemia. IL-6 antigen, demonstrated immunohistochemically, was increased in astrocytes from ischemic regions of gerbil brain. These data suggest that H/R enhances transcription of IL-6, resulting in increased translation and release of IL-6 antigen after the burst of ROI generated early during reoxygenation. Release of IL-6 from astrocytes could exert a paracrine neurotrophic effect in brain ischemia.
Maeda
Y
Y
Department of Immunoregulation, Osaka University, Suita City, Japan.
Matsumoto
M
M
Hori
O
O
Kuwabara
K
K
Ogawa
S
S
Yan
S D
SD
Ohtsuki
T
T
Kinoshita
T
T
Kamada
T
T
Stern
D M
DM
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D001921:Brain / Q000276:immunology / Q000502:physiology*; D002545:Brain Ischemia / Q000276:immunology / Q000503:physiopathology*; D002470:Cell Survival / Q000276:immunology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D017931:DNA Primers; D015870:Gene Expression; D015850:Interleukin-6 / Q000096:biosynthesis*; D002546:Ischemic Attack, Transient / Q000276:immunology / Q000503:physiopathology*; D017628:Microglia / Q000276:immunology; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D016716:PC12 Cells; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017077:Culture Media, Conditioned; D017931:DNA Primers; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha