GROWTH-HORMONE STIMULATES INTERFERON REGULATORY FACTOR-I GENE-EXPRESSION IN THE LIVER

Interferon regulatory factor-1 (IRF-1) is a transcription factor ident ified as part of the nuclear response to interferons. IRF-1 been shown to be activated by many cytokines, including PRL, and has been though t to play a role in PRL-regulated gene expression in several experimen tal systems, including the Nb2 T lymphoma cell line, where it was firs t characterized as a PRL-responsive gene. We now find that IRF-1 gene expression is rapidly activated in vivo by both PRL and GH treatment. A single ip injection of rat PRL to hypophysectomized female rats caus ed a transient increase in nascent hepatic nuclear IRF-1 RNA within 15 min of hormone treatment. The rise in IRF-1 transcripts was accompani ed by induction of nuclear protein binding to a DNA element from the p roximal IRF-1 promoter, as assessed by gel mobility shift assays; this element was shown previously to mediate PRL-activated gene transcript ion. GH treatment stimulated a greater and more sustained increase in nascent IRF-1 RNA than PRL, leading to accumulation of IRF-1 transcrip ts for up to 16 h after a single hormone injection. GH also caused a p ronounced induction of hepatic nuclear protein binding to the IRF-1 pr omoter element. Supershift experiments with specific antibodies showed that signal transducer and activator of transcription 1 (STAT1) and t o a lesser extent STAT3 were components of the GH-activated protein-DN A complexes. By contrast, these two STATs were not induced in the live r by PRL. Protein binding to the IRF-1 DNA element and IRF-1 gene acti vation by GH were not blunted by pretreatment with the protein synthes is inhibitor, cycloheximide, indicating that these hormonal effects ar e primary consequences of GH-activated signal transduction pathways. O ur results identify another component of the rapid nuclear response to GH, and support the idea that multiple primary and secondary signalin g pathways contribute to the acute actions of GH on gene expression.