IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFN gamma-responsive promoters in macrophages

IFN gamma, once called the macrophage-activating factor, stimulates many ge nes in macrophages, ultimately leading to the elicitation of innate immunit y. IFN gamma's functions depend on the activation of STAT1, which stimulate s transcription of IFN gamma-inducible genes through the GAS element. The I FN consensus sequence binding protein (icsb gamma or IFN regulatory factor 8), encoding a transcription factor of the IFN regulatory factor family, is one of such IFN gamma-inducible genes in macrophages. We found that macrop hages from ICSBP-/- mice were defective in inducing some IFN gamma-responsi ve genes, even though they were capable of activating STAT1 in response to IFN gamma. Accordingly, IFN gamma activation of luciferase reporters fused to the GAS element was severely impaired in ICSBP-/- macrophages, but trans fection of ICSBP resulted in marked stimulation of these reporters. Consist ent with its role in activating IFN gamma-responsive promoters, ICSBP stimu lated reporter activity in a GAS-specific manner, even in the absence of IF N gamma treatment, and in STAT1 negative cells. Indicative of a mechanism f or this stimulation, DMA affinity binding assays revealed that endogenous I CSBP was recruited to a multiprotein complex that bound to GAS. These resul ts suggest that ICSBP, when induced by IFN gamma through STAT1, in turn gen erates a second wave of transcription from GAS-containing promoters, thereb y contributing to the elicitation of IFN gamma's unique activities in immun e cells.