Biologic consequences of Stat1-independent IFN signaling

Although Stat1 is required for many IFN-dependent responses, recent work has shown that IFN gamma functions independently of Stat1 to affect the growth of tumor cells or immortalized fibroblasts. We now demonstrate that both IFN gamma and IFN alpha/beta regulate proliferative responses in cells of the mononuclear phagocyte lineage derived from Stat1-null mice. Using both representational difference analysis and gene arrays, we show that IFN gamma exerts its Stat1-independent actions on mononuclear phagocytes by regulating the expression of many genes. This result was confirmed by monitoring changes in expression and function of the corresponding gene products. Regulation of the expression of these genes requires the IFN gamma receptor and Jak1. The physiologic relevance of IFN-independent Statl-independent signaling was demonstrated by monitoring antiviral responses in Stat1-null mice. Thus, the IFN receptors engage alternative Statl-independent signaling pathways that have important physiological consequences.