Insulin-like growth factor-I stimulates dephosphorylation of ikappa B through the serine phosphatase calcineurin (protein phosphatase 2B).
Astrocytes represent the most abundant cell type of the adult nervous system. Under normal conditions, astrocytes participate in neuronal feeding and detoxification. However, following brain injury, local increases in inflammatory cytokines trigger a reactive phenotype in astrocytes during which these cells produce their own inflammatory cytokines and neurotoxic free radicals. Indeed, progression of this inflammatory reaction is responsible for most neurological damage associated with brain trauma. Insulin-like growth factor-I (IGF-I) protects neurons against a variety of brain pathologies associated with glial overproduction of proinflammatory cytokines. Here, we demonstrate that in astrocyte cultures IGF-I regulates NFkappaB, a transcription factor known to play a key role in the inflammatory reaction. IGF-I induces a site-specific dephosphorylation of IkappaBalpha (phospho-Ser(32)) in astrocytes. Moreover, IGF-I-mediated dephosphorylation of IkappaBalpha protects this molecule from tumor necrosis factor alpha (TNFalpha)-stimulated degradation; therefore, IGF-I also inhibits the nuclear translocation of NFkappaB (p65) induced by TNFalpha exposure. Finally, we show that dephosphorylation of IkappaBalpha by IGF-I pathways requires activation of calcineurin. Activation of this phosphatase is independent of phosphatidylinositol 3-kinase and mitogen-activated protein kinase. Thus, these data suggest that the therapeutic benefits associated with IGF-I treatment of brain injury are derived from both its positive effects on neuronal survival and inhibition of the glial inflammatory reaction.
Pons
S
S
Cellular and Molecular Neuroendocrinology Laboratory, Instituto Cajal de Neurobiologia, Consejo Superior de Investigaciones Cientificas, Av. Doctor Arce 37, Madrid E28002, Spain. pons@cajal.csic.es
Torres-Aleman
I
I
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020672:I-kappa B Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D010768:Phosphoserine; D007334:Insulin-Like Growth Factor I; D019703:Calcineurin