Insulin-like growth factor-I stimulates dephosphorylation of IκB 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 NF kappaB, a transcription factor known to play a key role in the inflammatory reaction. IGF-I induces a site-specific dephosphorylation of I kappaB alpha (phospho-Ser(32)) in astrocytes. Moreover, IGF-I-mediated dephosphorylation of I kappaB alpha protects this molecule from tumor necrosis factor cu (TNF alpha)-stimulated degradation; therefore, IGF-I also inhibits the nuclear translocation of NF kappaB (p65) induced by TNF alpha exposure. Finally, we show that dephosphorylation of I kappaB alpha 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.