ICSBP/IRF-8: its regulatory roles in the development of myeloid cells.
Interferon (IFN) consensus sequence binding protein (ICSBP)/IFN regulatory factor (IRF)-8 is an IFNgamma-inducible transcription factor of the IRF family and regulates transcription through multiple target DNA elements, such as IFN-stimulated response element (ISRE), Ets/IRF composite element, and IFN-gamma activation site (GAS). ICSBP(-/-) mice are immunodeficient and susceptible to various pathogens. They have defects in the macrophage function, including the ability to induce interleukin-12 (IL-12) p40 and some IFN-gamma-responsible genes. In addition, ICSBP(-/-) mice develop a chronic myelogenous leukemia (CML)-like syndrome, where a systemic expansion of granulocytes is followed by a fatal blast crisis. ICSBP(-/-) mice harbor an increased number of myeloid progenitor cells, and the -/- progenitors preferentially give rise to granulocytes, although they cannot efficiently generate another descendant of the myeloid lineage, macrophages. Studies with myeloid progenitor cells have shown that ICSBP drives their differentiation toward macrophage, whereas it inhibits granulocyte differentiation. Furthermore, myeloid cells from ICSBP(-/-) mice are resistant to apoptosis. These results illustrate the mechanism by which the loss of ICSBP leads to immunodeficiency and CML-like syndrome and suggest ICSBP's critical role in the development of myeloid cells.
Tamura
Tomohiko
T
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. tamurat@mail.nih.gov
Ozato
Keiko
K
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D006801:Humans; D050835:Interferon Regulatory Factors; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
D050835:Interferon Regulatory Factors; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8