Insulin-like growth factor-I stimulates dephosphorylation of I kappa B through the serine phosphatase calcineurin (protein phosphatase 2B)

Astrocytes represent the most abundant cell type of the adult nervous syste m. Under normal conditions, astrocytes participate in neuronal feeding and detoxification. However, following brain injury, local increases in inflamm atory cytokines trigger a reactive phenotype in astrocytes during which the se cells produce their own inflammatory cytokines and neurotoxic free radic als. Indeed, progression of this inflammatory reaction is responsible for m ost neurological damage associated with brain trauma. Insulin-Like growth f actor-I (IGF-I) protects neurons against a variety of brain pathologies ass ociated with glial overproduction of proinflammatory cytokines. Here, we de monstrate that in astrocyte cultures IGF-I regulates NF kappaB, a transcrip tion factor known to play a key role in the inflammatory reaction. IGF-I in duces a site-specific dephosphorylation of I kappaB alpha (phospho-Ser(32)) in astrocytes. Moreover, IGF-I-mediated dephosphorylation of I kappaB alph a protects this molecule from tumor necrosis factor cu (TNF alpha)-stimulat ed degradation; therefore, IGF-I also inhibits the nuclear translocation of NF kappaB (p65) induced by TNF alpha exposure. Finally, we show that depho sphorylation of I kappaB alpha by IGF-I pathways requires activation of cal cineurin. Activation of this phosphatase is independent of phosphatidylinos itol 3-kinase and mitogen-activated protein kinase. Thus, these data sugges t that the therapeutic benefits associated with IGF-I treatment of brain in jury are derived from both its positive effects on neuronal survival and in hibition of the glial inflammatory reaction.