CILIARY NEUROTROPHIC FACTOR ACTIVATES JAK STAT SIGNAL-TRANSDUCTION CASCADE AND INDUCES TRANSCRIPTIONAL EXPRESSION OF GLIAL FIBRILLARY ACIDIC PROTEIN IN GLIAL-CELLS/

In recent reports, ciliary neurotrophic factor (CNTF) has been implica ted as an injury factor involved in regulating astrogliosis in the CNS . In this study, we used a rat oligodendroglial progenitor cell line t hat is highly responsive to CNTF to examine CNTF-induced alterations t hat may play a role in activation of the glial fibrillary acidic prote in (GFAP) gene, We determined that CNTF induces the transient transloc ation of Stat1 alpha/p91 to the nucleus, This nuclear translocation wa s followed by GFAP promoter activation and an up-regulation of GFAP mR NA and protein, Levels of CNTF-alpha receptor mRNA, however, were unaf fected by addition of the ligand. Transfection studies using an upstre am 5'-flanking, 1.9-kb rat GFAP promoter linked to a luciferase report er gene revealed CNTF-induced transcriptional activation within 1 h of ligand exposure. Moreover, serial-deleted constructs identified a dis tal (-1,857 to -1,546 bp) and a proximal (-384 to -106 bp) region as b eing important for CNTF-induced GFAP promoter activation. These two re gions showed a strong degree of overlap for CNTF- and serum-induced ac tivation of the GFAP gene. Analysis of the two regions revealed severa l cis-elements that are thought to be involved in GFAP regulation and/ or the regulation of other genes by members of the interleukin-6 famil y of cytokines. Moreover, we are the first to report the presence of s everal putative CNTF-responsive elements within our identified distal and proximal regions in the GFAP gene promoter.