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Gene Review

IRF8  -  interferon regulatory factor 8

Homo sapiens

Synonyms: H-ICSBP, ICSBP, ICSBP1, IMD32A, IMD32B, ...
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Disease relevance of IRF8


High impact information on IRF8

  • Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements [5].
  • Mice with a null mutation of ICSBP exhibit two prominent phenotypes related to previously described activities of the IRF family [6].
  • The second is deregulated hematopoiesis in both ICSBP-/- and ICSBP+/- mice that manifests as a syndrome similar to human chronic myelogenous leukemia [6].
  • These results suggest a novel role for ICSBP in regulating the proliferation and differentiation of hematopoietic progenitor cells [6].
  • These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6 [7].

Biological context of IRF8


Anatomical context of IRF8

  • In this work, we find that ICSBP-deficient macrophages are highly defective in the production of IL-12 [11].
  • To gain a broader insight of the capacity of ICSBP to interact with other factors, yeast two-hybrid screens were performed using ICSBP-IAD as a bait against a B-cell cDNA library [10].
  • Interferon consensus sequence-binding protein (ICSBP) is a member of the interferon regulatory factors (IRF) that has a pivotal role in mediating resistance to pathogenic infections in mice and in promoting the differentiation of myeloid cells [10].
  • Chicken ICSBP was found to be expressed in several embryonic tissues, and both chicken IRF-1 and ICSBP were strongly induced in chicken fibroblasts by IFN treatment, supporting the involvement of these factors in IFN-regulated gene expression [12].
  • In this study, anti-ICSBP peptide Abs were used to quantify and localize ICSBP in murine peritoneal exudate macrophages [13].

Associations of IRF8 with chemical compounds

  • Taken together, these results suggest that ICSBP is a negative regulatory factor capable of repressing transcription of target genes induced by IFN, retinoic acid, or IRF-1 [1].
  • Trip15 was identified as a specific interacting factor with ICSBP in yeast cells, which was also confirmed by in vitro glutathione S-transferase pull-down assays and by coimmunoprecipitation studies in COS7 cells [10].
  • In vitro studies demonstrated that direct binding of ICSBP to DNA is prevented by tyrosine (Tyr) phosphorylation [14].
  • Northern and Western blotting showed that decitabine induced transcription of c-jun but not PU.1, while VD3 increased PU.1, IRF8, and C/EBPbeta but not c-jun [15].
  • As a suitable mechanism for these effects, bortezomib was found to down-regulate MyD88, an essential adaptor for TLR signaling, and to relieve LPS-induced activation of NF-kappaB, IRF-3, and IRF-8 and of the MAP kinase pathway [16].

Physical interactions of IRF8


Regulatory relationships of IRF8

  • H-ICSBP is expressed exclusively in cell lines of hematopoietic origin [9].
  • ICSBP is expressed constitutively in hematopoietic cells and its expression is further induced by IFN-gamma [19].
  • Consistent with these results, we find JAK2 activation is sufficient to induce ICSBP interaction with the HAF1 element and abolish HoxA10 binding to the CYBBrepressor element [20].

Other interactions of IRF8


Analytical, diagnostic and therapeutic context of IRF8

  • Further, electrophoretic mobility shift assays show that this interaction greatly enhances the otherwise very low binding affinity of ICSBP to the ISRE [8].
  • Indirect immunofluorescence also demonstrated ICSBP to be an IFN-gamma-inducible protein that is strongly localized to the nucleus [13].
  • The ubiquitination of IRF-8 was shown by co-immunoprecipitation from RAW264.7 macrophages retrovirally transduced with IRF-8 and hemagglutinin-ubiquitin [22].
  • ICSBP expression represents a novel means of stimulating a host immune response to BCR/ABL(+) leukemia cells and a potential strategy for immunotherapy of CML [23].


  1. Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Nelson, N., Marks, M.S., Driggers, P.H., Ozato, K. Mol. Cell. Biol. (1993) [Pubmed]
  2. Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. Sharf, R., Azriel, A., Lejbkowicz, F., Winograd, S.S., Ehrlich, R., Levi, B.Z. J. Biol. Chem. (1995) [Pubmed]
  3. Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-alpha. Schmidt, M., Hochhaus, A., Nitsche, A., Hehlmann, R., Neubauer, A. Blood (2001) [Pubmed]
  4. The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. Zhu, C., Saberwal, G., Lu, Y., Platanias, L.C., Eklund, E.A. J. Biol. Chem. (2004) [Pubmed]
  5. Transcriptional control of early B cell development. Busslinger, M. Annu. Rev. Immunol. (2004) [Pubmed]
  6. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Holtschke, T., Löhler, J., Kanno, Y., Fehr, T., Giese, N., Rosenbauer, F., Lou, J., Knobeloch, K.P., Gabriele, L., Waring, J.F., Bachmann, M.F., Zinkernagel, R.M., Morse, H.C., Ozato, K., Horak, I. Cell (1996) [Pubmed]
  7. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. Lee, C.H., Melchers, M., Wang, H., Torrey, T.A., Slota, R., Qi, C.F., Kim, J.Y., Lugar, P., Kong, H.J., Farrington, L., van der Zouwen, B., Zhou, J.X., Lougaris, V., Lipsky, P.E., Grammer, A.C., Morse, H.C. J. Exp. Med. (2006) [Pubmed]
  8. Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Bovolenta, C., Driggers, P.H., Marks, M.S., Medin, J.A., Politis, A.D., Vogel, S.N., Levy, D.E., Sakaguchi, K., Appella, E., Coligan, J.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. Weisz, A., Marx, P., Sharf, R., Appella, E., Driggers, P.H., Ozato, K., Levi, B.Z. J. Biol. Chem. (1992) [Pubmed]
  10. Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome. Cohen, H., Azriel, A., Cohen, T., Meraro, D., Hashmueli, S., Bech-Otschir, D., Kraft, R., Dubiel, W., Levi, B.Z. J. Biol. Chem. (2000) [Pubmed]
  11. Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. Liu, J., Guan, X., Tamura, T., Ozato, K., Ma, X. J. Biol. Chem. (2004) [Pubmed]
  12. Chicken interferon consensus sequence-binding protein (ICSBP) and interferon regulatory factor (IRF) 1 genes reveal evolutionary conservation in the IRF gene family. Jungwirth, C., Rebbert, M., Ozato, K., Degen, H.J., Schultz, U., Dawid, I.B. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  13. Regulation of IFN-gamma-induced nuclear expression of IFN consensus sequence binding protein in murine peritoneal macrophages. Politis, A.D., Ozato, K., Coligan, J.E., Vogel, S.N. J. Immunol. (1994) [Pubmed]
  14. Phosphorylation events modulate the ability of interferon consensus sequence binding protein to interact with interferon regulatory factors and to bind DNA. Sharf, R., Meraro, D., Azriel, A., Thornton, A.M., Ozato, K., Petricoin, E.F., Larner, A.C., Schaper, F., Hauser, H., Levi, B.Z. J. Biol. Chem. (1997) [Pubmed]
  15. Decitabine and Vitamin D3 differentially affect hematopoietic transcription factors to induce monocytic differentiation. Koschmieder, S., Agrawal, S., Radomska, H.S., Huettner, C.S., Tenen, D.G., Ottmann, O.G., Berdel, W.E., Serve, H.L., M??ller-Tidow, C. Int. J. Oncol. (2007) [Pubmed]
  16. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Nencioni, A., Schwarzenberg, K., Brauer, K.M., Schmidt, S.M., Ballestrero, A., Grünebach, F., Brossart, P. Blood (2006) [Pubmed]
  17. IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. Zhao, J., Kong, H.J., Li, H., Huang, B., Yang, M., Zhu, C., Bogunovic, M., Zheng, F., Mayer, L., Ozato, K., Unkeless, J., Xiong, H. J. Biol. Chem. (2006) [Pubmed]
  18. PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. Huang, W., Horvath, E., Eklund, E.A. J. Biol. Chem. (2007) [Pubmed]
  19. IFN consensus sequence binding protein (ICSBP) is a conditional repressor of IFN inducible promoters. Weisz, A., Kirchhoff, S., Levi, B.Z. Int. Immunol. (1994) [Pubmed]
  20. JAK2 is necessary and sufficient for interferon-gamma-induced transcription of the gene encoding gp91PHOX. Kakar, R., Kautz, B., Eklund, E.A. J. Leukoc. Biol. (2005) [Pubmed]
  21. PU.1/Interferon Regulatory Factor interactions: mechanisms of transcriptional regulation. Marecki, S., Fenton, M.J. Cell Biochem. Biophys. (2000) [Pubmed]
  22. Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. Xiong, H., Li, H., Kong, H.J., Chen, Y., Zhao, J., Xiong, S., Huang, B., Gu, H., Mayer, L., Ozato, K., Unkeless, J.C. J. Biol. Chem. (2005) [Pubmed]
  23. Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Deng, M., Daley, G.Q. Blood (2001) [Pubmed]
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