Gene modulation and immunoregulatory roles of interferon gamma

Interferon-gamma (IFNgamma) is a central regulator of the immune response and signals via the Janus Activated Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway. Phosphorylated STAT1 homodimers translocate to the nucleus, bind to Gamma Activating Sequence (GAS) and recruit additional factors to modulate gene expression. A bioinformatics analysis revealed that greater number of putative promoters of immune related genes and also those not directly involved in immunity contain GAS compared to response elements (RE) for Interferon Regulatory Factor (IRF)1, Nuclear factor kappa B (NFkappaB) and Activator Protein (AP)1. GAS is present in putative promoters of well known IFNgamma-induced genes, IRF1, GBP1, CXCL10, and other genes identified were TLR3, VCAM1, CASP4, etc. Analysis of three microarray studies revealed that the expression of a subset of only GAS containing immune genes were modulated by IFNgamma. As a significant correlation exists between GAS containing immune genes and IFNgamma-regulated gene expression, this strategy may identify novel IFNgamma-responsive immune genes. This analysis is integrated with the literature on the roles of IFNgamma in mediating a plethora of functions: anti-microbial responses, antigen processing, inflammation, growth suppression, cell death, tumor immunity and autoimmunity. Overall, this review summarizes our present knowledge on IFNgamma mediated signaling and functions.