Regulation of IFN consensus sequence binding protein expression in murine macrophages

Recent work has demonstrated that the transcription fatter, IFN consensus s equence binding protein (ICSBP), plays a critical role in the capacity of m ice to control infection with Toxoplasma gondii and Leishmania major, agent s that require highly activated macrophages for, their elimination, In this report the regulation of ICSBP mRNA and protein were analyzed in murine ma crophages stimulated with LPS and/or IFN-gamma. Like induction of leishmani acidal activity, LPS and IFN-gamma, synergize to induce ICSBP mRNA and prot ein. Deletion analysis of the ICSBP promoter identified regions that were I FN-gamma responsive, regions that mediate the ability of LPS and IFN-gamma to activate this promoter synergistically, as well as regions that normally repress ICSBP transcription. Finally, exogenous expression of ICSBP, found in previous studies to down-regulate MHC I gene expression, failed to repr ess basal or IFN-gamma-induced ICSBP transcription, This demonstrates that ICSBP can selectively suppress the expression of IFN-responsive genes. Thes e findings extend in a significant way our understanding of the regulation of ICSBP by LPS and IFN-gamma and provide important clues as to its role in macrophage activation.