02971nas a2200601   4500000000100000008004100001260001600042653001200058653002400070653003000094653001400124653001400138653000800152653002500160653001900185653002000204653002000224653001600244653001100260653002100271653003400292653002100326653003900347653002400386653001600410653000900426653001900435653001800454653002800472653003200500653002300532653002900555653002100584653002600605653001700631653003300648100002200681700001400703700001100717700001300728700001300741700001300754700001200767700001300779700001300792700001200805700001100817245010700828300001300935490000800948520139900956022001402355       2003                            d  c2003 Nov 0710aAnimals10aAutoimmune Diseases10aCation Transport Proteins10aCell Line10aCOS Cells10aDNA10aDNA-Binding Proteins10aDrug Synergism10aGene Expression10aGenetic Vectors10aHL-60 Cells10aHumans10aImmunity, Innate10aInterferon Regulatory Factors10aInterferon-gamma10aKruppel-Like Transcription Factors10aLipopolysaccharides10aMacrophages10aMice10aMice, Knockout10aNIH 3T3 Cells10aProto-Oncogene Proteins10aRecombinant Fusion Proteins10aRepressor Proteins10aSaccharomyces cerevisiae10aTrans-Activators10aTranscription Factors10aTransfection10aTwo-Hybrid System Techniques1 aAlter-Koltunoff M1 aEhrlich S1 aDror N1 aAzriel A1 aEilers M1 aHauser H1 aBowen H1 aBarton H1 aTamura T1 aOzato K1 aLevi B00aNramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1.  a44025-320 v2783 a<p>Natural resistance-associated macrophage protein 1 (Nramp1) is a proton/divalent cation antiporter exclusively expressed in monocyte/macrophage cells with a unique role in innate resistance to intraphagosomal pathogens. In humans, it is linked to several infectious diseases, including leprosy, pulmonary tuberculosis, visceral leishmaniasis, meningococcal meningitis, and human immunodeficiency virus as well as to autoimmune diseases such as rheumatoid arthritis and Crohn's disease. Here we demonstrate that the restricted expression of Nramp1 is mediated by the macrophage-specific transcription factor IRF-8. This factor exerts its activity via protein-protein interaction, which facilitates its binding to target DNA. Using yeast two-hybrid screen we identified Myc Interacting Zinc finger protein 1 (Miz-1) as new interacting partner. This interaction is restricted to immune cells and takes place on the promoter Nramp1 in association with PU.1, a transcription factor essential for myelopoiesis. Consistent with these data, IRF-8 knockout mice are sensitive to a repertoire of intracellular pathogens. Accordingly, IRF-8-/- mice express low levels of Nramp1 that can not be induced any further. Thus, our results explain in molecular terms the role of IRF-8 in conferring innate resistance to intracellular pathogens and point to its possible involvement in autoimmune diseases.</p>  a0021-9258