Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages.
IFN signaling is mediated by binding of IFNs to their receptors and subsequent activation of Janus tyrosine kinase (JAK)-STAT signaling pathway. Stimulation of cells with IFN-alpha leads to the assembly of IFN-stimulated gene factor 3 transcription factor complex formed by STAT1, STAT2, and p48 protein. IFN-gamma signaling is mediated by homodimeric STAT1 protein. Although these signaling molecules are expressed constitutively, there is also evidence of transcriptional regulation by IFNs. We have characterized the expression of STAT and IFN regulatory factor (IRF) family transcription factors in primary human blood mononuclear cells and macrophages in response to IFN-alpha and IFN-gamma stimulation. We show that IFN-alpha and IFN-gamma rapidly and efficiently enhanced STAT1, STAT2, p48, and IRF-1 gene expression. IFN-gamma induced IRF-1 gene expression more strongly than IFN-alpha. Stimulation experiments in the presence of protein synthesis inhibitor, cycloheximide, suggested that these genes were activated directly by IFNs. IRF-2 gene was apparently only weakly responsive to IFNs in these cells. When macrophages were pretreated with low doses of IFN-gamma and then stimulated with IFN-alpha, clearly enhanced formation of specific transcription factor complexes was detected. This suggests that higher intracellular levels of STAT1, STAT2, and p48 protein may result in enhanced signal transduction for cytokines utilizing these transcription factors.
Lehtonen
A
A
Department of Virology, National Public Health Institute, Helsinki, Finland.
Matikainen
S
S
Julkunen
I
I
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007372:Interferons / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D007372:Interferons