Biologic consequences of Stat1-independent IFN signaling

Although Stat1 is required for many IFN-dependent responses, recent work ha s shown that IFN gamma functions independently of Stat1 to affect the growt h of tumor cells or immortalized fibroblasts. We now demonstrate that both IFN gamma and IFN alpha/beta regulate proliferative responses in cells of t he mononuclear phagocyte lineage derived from Stat1-null mice. Using both r epresentational difference analysis and gene arrays, we show that IFN gamma exerts its Stat1-independent actions on mononuclear phagocytes by regulati ng the expression of many genes. This result was confirmed by monitoring ch anges in expression and function of the corresponding gene products. Regula tion of the expression of these genes requires the IFN gamma receptor and J ak1. The physiologic relevance of IFN-independent Statl-independent signali ng was demonstrated by monitoring antiviral responses in Stat1-null mice. T hus, the IFN receptors engage alternative Statl-independent signaling pathw ays that have important physiological consequences.