Regulation of cellular gene expression by interferon-gamma: involvement of multiple pathways

Interferons (IFNs) classified as type I (IFN-alpha and -beta) and type II (IFN-gamma) interact with different receptors and regulate the expression of a number of genes in common, whereas the expression of certain other genes is regulated differentially by the type I or type II IFNs. Regulation of cellular gene expression by IFN-gamma was studied with the help of two cDNA clones (called C5-4 and C13) isolated in our laboratory and cDNA clones for human leukocyte antigen (HLA) class I (HLA-B) and class II (HLA-DR alpha, -DR beta) genes. The results indicate that IFN-gamma induced the expression of the cognate genes, but in different manners. IFN-gamma induced the transcription of all four genes as determined by nuclear run-on transcription analyses, but the induction of C5-4 genes transcription was inhibited by cycloheximide and anisomycin, indicating that some newly synthesized protein, presumably induced by IFN-gamma, was required for the transcriptional activation of the C5-4 gene. On the contrary, IFN-gamma-induced transcription of HLA class I, class II and C13 genes was unaffected by cycloheximide or anisomycin. However, these inhibitors completely blocked the accumulation of the HLA class II gene transcripts, but not HLA class I or C13 gene transcripts. Results suggest that some newly synthesized protein factor was required for IFN-gamma-induced accumulation of HLA class II gene transcripts and played a role at a step subsequent to the transcriptional activation by IFN-gamma. Evidence was obtained which suggests that the putative protein factor(s) required was induced by IFN-gamma. These studies indicate that IFN-gamma regulates the expression of cellular genes through multiple pathways.