| To protect cells against viral infection, type I interferons (IFN-alpha, IFN-beta) transduce signals through STAT1 and STAT2 to activate gene expression. On the other hand, host defense against intracellular pathogens requires a cellular immune response mediated by IFN-gamma, a unique interferon that signals solely through STAT1. IFN-gamma induces critical factors such as IRF-1, a transcription factor with diverse inflammatory and antiviral responses, and CIITA, a master regulator of class II MHC expression. Even though both interferon families activate STAT1, IFN-alpha has never been shown to induce MHC II expression. To further understand the interplay and consequences of interferon signaling we examined the role of STAT2 in class II expression. We discovered that, whereas IFN-alpha had no effect in increasing MHC II expression in wild type macrophages, in the absence of STAT2, class II surface expression in both peritoneal and bone marrow-derived macrophages was significantly upregulated in response to IFN-alpha. This induction still required STAT1 and CIITA, and Northern blotting confirmed that wild type macrophages treated with IFN-alpha were not conducive to CIITA induction. Despite these findings, further analysis of STAT1-driven gene expression by Northern blotting and electrophoretic mobility shift assays showed that IFN-alpha is normally quite capable of inducing other IFN-gamma-dependent genes, including IRF-1. However, IFN-alpha treatment of wild type cells led to a rapid disruption in IRF-1 protein stability whereas STAT2-null cells displayed sustained levels of IRF-1. This study suggests that by regulating IRF-1 levels, STAT2 engages a negative feedback pathway that represses the ability of IFN-alpha to upregulate MHC II, a critical molecule for antigen presentation, and this mechanism underscores the importance for potent inflammatory cells such as macrophages to distinguish between IFN-alpha/beta and IFN-gamma responses. |
