Activation of the JAK/STAT pathway following transient focal cerebral ischemia: Signaling through Jak1 and Stat3 in astrocytes

JAK/STAT is one of the pathways bearing signals from the cell membrane to t he nucleus in response to extracellular growth factors and cytokines. In th e present study, we examined the cellular distribution of Jak1 and Stat3, a nd activation of the JAK/STAT pathway following transient focal cerebral is chemia in the rat. Jak1 was mainly seen in white matter astrocytes and in c ertain neurons. Notably, large pyramidal neurons of cortical layer V showed the highest neuronal Jak1 expression within cerebral cortex and, in additi on, expressed Stat3 indicating that the JAK/STAT pathway is involved in sig naling in the corticofugal projection system. Shortly following ischemia, J ak1 immunoreactive astrocytes located in the ipsilateral neighbouring white matter and ischemic cortex and striatum showed nuclear translocation of St at3. These features were maintained in large reactive astrocytes that surro unded the infarct from 3 to 7 days. At these later times, the abundant reac tive microglia/macrophages were strongly immunoreactive to Stat3 and, to a lesser extent, Jak1. Two main protein complexes showing DNA binding activit y at the sis-inducible element site were found under basal conditions, foll owed by changes in this pattern following ischemia concomitant with neurona l cell loss and, activation of glia. This study showed basal cerebral activ ity of JAK/STAT signaling pathway, involving Jak1 and Stat3 proteins, and s elective activation following ischemia. It is suggested that the kinase act ivity of Jak1 mediates nuclear translocation of Stat3 in astrocytes, and th at this signaling pathway is involved in the astroglial response to focal c erebral ischemia. (C) 2000 Wiley-Liss, Inc.