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Cited by 183interferon and immune responsesAcute Myeloid Leukemia ResearchImmunodeficiency and Autoimmune Disorders

Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells

Tamura, Tomohiko, Ozato, Keiko·2002·Journal of Interferon & Cytokine Research
DOI 10.1089/107999002753452755
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

ICSBP/IRF-8 is an IFN-γ–inducible transcription factor of the IRF family that regulates myeloid cell development, acting as either a repressor or activator depending on the target DNA element. Loss of ICSBP in mice causes immunodeficiency (defective macrophage/IL-12 function) and a chronic myelogenous leukemia (CML)-like syndrome.

Key findings

  • ICSBP⁻/⁻ mice are immunodeficient and susceptible to pathogens controlled by type II IFN (vaccinia, lymphocytic choriomeningitis virus, *Listeria monocytogenes*, *Yersinia enterocolitica*, *Leishmania major*, *Toxoplasma gondii*), but survive vesicular stomatitis virus or influenza A.
  • ICSBP⁻/⁻ mice develop a CML-like syndrome: systemic expansion/infiltration of granulocytes (predominantly mature neutrophils) in essentially 100% of mice, with lymphadenopathy and hepatosplenomegaly; approximately 33% of ICSBP⁻/⁻ and 9% of ICSBP⁺/⁻ mice died by 50 weeks of age with features of blast crisis, including leukocytosis (>100,000/μl).
  • ICSBP directs myeloid progenitors toward macrophage differentiation and inhibits granulocyte growth/differentiation; ICSBP⁻/⁻ myeloid cells show reduced spontaneous apoptosis and reduced sensitivity to DNA-damage–induced apoptosis.
  • ICSBP activates IL-12 p40 transcription (via the Ets site, with IRF-1 synergy) and potentiates Stat1-dependent activation of IFN-γ–responsive GAS-containing promoters; ICSBP⁻/⁻ macrophages are defective in inducing FcγRI and iNOS.

Methods

  • Narrative review synthesizing published and unpublished work on ICSBP/IRF-8, its structure, target elements, interacting proteins, and role in myeloid development.
  • Evidence drawn from ICSBP⁻/⁻ and ICSBP⁺/⁻ mice, established ICSBP⁻/⁻ myeloid progenitor cell lines (e.g., Tot2), retroviral ICSBP transduction, colony-forming assays with GM-CSF/G-CSF/M-CSF, DNA affinity binding assays, and transfected luciferase reporters.
  • No new primary data or formal meta-analysis are presented; the paper is a synthesis of cited studies.

Limitations

  • Stated: many studies relied on activities of transfected reporters containing ISRE or EICE, so it remains important to determine whether ICSBP regulates endogenous genes through these elements; immediate target genes that trigger differentiation in progenitor cells have not been identified.
  • Stated: some cited observations are unpublished (e.g., ICSBP expression in Lin⁻ progenitors, additional IL-12 p40 promoter element, TEL interaction, dendritic cell maturation).
  • Evident from the text: as a review, conclusions depend on the cited primary studies, and several mechanistic claims (e.g., ICSBP–IRF-4 compensation) are proposed as possibilities rather than demonstrated.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/107999002753452755

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 124 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP is expressed in lineage marker-negative (Lin-) hematopoietic progenitor cells in bone marrow.

    “Recently, we found that ICSBP is expressed in lineage marker-negative (Lin 2 ) hematopoietic progenitor cells in bone marrow.”
    Quote in the paperNot a substantial claim
  • Findingcitation
    § ICSBP regulation of apoptosis in myeloid cells

    Apoptosis in ICSBP−/− thymocytes is unaffected.

    “In contrast, apoptosis in ICSBP 2 / 2 thymocytes was unaffected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] 56. GABRIELE, L., PHUNG, J., FUKUMOTO, J., SEGAL, D., WANG, I.M., GIANNAKAKOU, P., GIESE, N.A., OZATO, K., and MORSE, H.C., 3rd (1999). Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 190, 411-421. source

      Not checked in the free run.

  • Findingcitation
    § ICSBP regulation of apoptosis in myeloid cells

    Cells overexpressing ICSBP had enhanced expression of caspase-3 precursor protein.

    “Cells overexpressing ICSBP had enhanced expression of caspase-3 precursor protein and decreased expression of Bcl-X(L).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] 56. GABRIELE, L., PHUNG, J., FUKUMOTO, J., SEGAL, D., WANG, I.M., GIANNAKAKOU, P., GIESE, N.A., OZATO, K., and MORSE, H.C., 3rd (1999). Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 190, 411-421. source

      Not checked in the free run.

  • Findingcitation
    § ICSBP regulation of apoptosis in myeloid cells

    Overexpression of ICSBP in U937 cells increased their sensitivity to apoptosis induced by etoposide, LPS plus ATP, or rapamycin.

    “Overexpression of ICSBP in the human U937 myelomonoblastic leukemia cell line enhanced the rate of spontaneous apoptosis and increased the sensitivity to apoptosis induced by etoposide, LPS plus ATP, or rapamycin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] 56. GABRIELE, L., PHUNG, J., FUKUMOTO, J., SEGAL, D., WANG, I.M., GIANNAKAKOU, P., GIESE, N.A., OZATO, K., and MORSE, H.C., 3rd (1999). Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 190, 411-421. source

      Not checked in the free run.

  • Findingcitation
    § ICSBP regulation of apoptosis in myeloid cells

    Cells overexpressing ICSBP had decreased expression of Bcl-X(L).

    “Cells overexpressing ICSBP had enhanced expression of caspase-3 precursor protein and decreased expression of Bcl-X(L).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] 56. GABRIELE, L., PHUNG, J., FUKUMOTO, J., SEGAL, D., WANG, I.M., GIANNAKAKOU, P., GIESE, N.A., OZATO, K., and MORSE, H.C., 3rd (1999). Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 190, 411-421. source

      Not checked in the free run.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP expression is relatively high in macrophages and very low in granulocytes.

    “The expression is relatively high in macrophages and very low in granulocytes (H. Tsujimura, T. Nagamura-Inoue, T.T., and K.O., unpublished observations).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Transcriptional pathways regulated by ICSBP

    PU.1−/− mice do not produce mature macrophages and have very few granulocytes.

    “PU.1 2 / 2 mice do not produce mature macrophages and have very few granulocytes. (60)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] 60. SIMON, M.C. (1998). PU.1 and hematopoiesis: lessons learned from gene targeting experiments. Semin. Immunol. 10, 111-118. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given
    § Transcriptional pathways regulated by ICSBP

    Neither IRF-1−/−, IRF-2−/−, nor IRF-1−/−IRF-2−/− mice were reported to have defects in myeloid differentiation.

    “Although neither IRF-1 2 / 2 , IRF-2 2 / 2 , nor IRF-1 2 / 2 /IRF-2 2 / 2 mice were reported to have defects in myeloid differentiation,”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Transcriptional pathways regulated by ICSBP

    IRF-4−/− mice have severe defects in B and T lymphocyte function.

    “IRF-4 2 / 2 mice develop progressive generalized lymphadenopathy and have severe defects in B and T lymphocyte function. (65)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] 65. MITTRUCKER, H.W., MATSUYAMA, T., GROSSMAN, A., KUNDIG, T.M., POTTER, J., SHAHINIAN, A., WAKEHAM, A., PATTERSON, B., OHASHI, P.S., and MAK, T.W. (1997). Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540-543. Address reprint requests to: Dr. Tomohiko Tamura Laboratory of Molecular Growth Regulation National Institute of Child Health and Human Development National Institutes of Health Building 6, Room 416 9000 Rockville Pike Bethesda, MD 20892-2753 Tel: (301) 496-2518 Fax: (301) 480-9354 E-mail: tamurat@mail.nih.gov Accepted 1 August source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Transcriptional pathways regulated by ICSBP

    IRF-4−/− mice develop progressive generalized lymphadenopathy.

    “IRF-4 2 / 2 mice develop progressive generalized lymphadenopathy and have severe defects in B and T lymphocyte function. (65)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] 65. MITTRUCKER, H.W., MATSUYAMA, T., GROSSMAN, A., KUNDIG, T.M., POTTER, J., SHAHINIAN, A., WAKEHAM, A., PATTERSON, B., OHASHI, P.S., and MAK, T.W. (1997). Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540-543. Address reprint requests to: Dr. Tomohiko Tamura Laboratory of Molecular Growth Regulation National Institute of Child Health and Human Development National Institutes of Health Building 6, Room 416 9000 Rockville Pike Bethesda, MD 20892-2753 Tel: (301) 496-2518 Fax: (301) 480-9354 E-mail: tamurat@mail.nih.gov Accepted 1 August source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § NOTE ADDED IN PROOF

    The Ets transcription factor TEL interacts with ICSBP to be recruited onto the ISRE.

    “Recently, we found that another Ets transcription factor, TEL, interacts with ICSBP to be recruited onto the ISRE (C. Gongora, T. Kuwata, T.T., and K.O., submitted for publication).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § ABSTRACT

    ICSBP-/- mice are immunodeficient and susceptible to various pathogens.

    “ICSBP 2 / 2 mice are immunodeficient and susceptible to various pathogens.”
    • Also stated in: § IMMUNODEFICIENCY OF ICSBP 2 / 2 MICE · plain
      “ICSBP 2 / 2 mice were found to display increased susceptibility to infection with various pathogens, control of which requires type II IFN (IFNg )-mediated immunity.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [37] 37. HOLTSCHKE, T., LOHLER, 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., 3rd, OZATO, K., and HORAK, I. (1996). Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307-317. source

      Not checked in the free run.

    • cites [38] 38. FEHR, T., SCHOEDON, G., ODERMATT, B., HOLTSCHKE, T., SCHNEEMANN, M., BACHMANN, M.F., MAK, T.W., HORAK, I., and ZINKERNAGEL, R.M. (1997). Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis. J. Exp. Med. 185, 921-931. source

      Not checked in the free run.

    • cites [39] 39. HEIN, J., KEMPF, V.A., DIEBOLD, J., BUCHELER, N., PREGER, S., HORAK, I., SING, A., KRAMER, U., and AUTENRIETH, I.B. (2000). Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica . Infect. Immun. 68, 1408-1417. source

      Not checked in the free run.

    • cites [40] 40. GIESE, N.A., GABRIELE, L., DOHERTY, T.M., KLINMAN, D.M., TADESSE-HEATH, L., CONTURSI, C., EPSTEIN, S.L., and MORSE, H.C., 3rd (1997). Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535-1546. source

      Not checked in the free run.

    • cites [41] 41. SCHARTON-KERSTEN, T., CONTURSI, C., MASUMI, A., SHER, A., and OZATO, K. (1997). Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523-1534. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ABSTRACT

    ICSBP/IRF-8 is an IFN-γ-inducible transcription factor of the IRF family that regulates transcription through multiple target DNA elements, including ISRE, EICE, and GAS.

    “Interferon (IFN) consensus sequence binding protein (ICSBP)/IFN regulatory factor (IRF)-8 is an IFN g -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 IFNg activation site (GAS).”
    • Also stated in: § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP · hedged
      “ICSBP is expressed in the hematopoietic cells, including cells of the monocyte/macrophage lineage, B lymphocytes, and activated T lymphocytes, and is inducible by IFNg in these cells, suggesting its role in immune cells. (6,9-13)”
    • Also stated in: § TARGET DNA ELEMENTS, INTERACTING PROTEINS, AND REGULATION OF TRANSCRIPTION · hedged
      “Recent studies indicate that ICSBP can act on a wide range of target elements even beyond the IRS, such as the Ets site in IL-12 p40 promoter and the IFNg activation site (GAS). (15,34)”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [6] 6. WEISZ, A., MARX, P., SHARF, R., APPELLA, E., DRIGGERS, P.H., OZATO, K., and LEVI, B.-Z. (1992). Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. J. Biol. Chem. 267, 25589-25596. source

      Not checked in the free run.

    • cites [9] 9. POLITIS, A.D., SIVO, J., DRIGGERS, P.H., OZATO, K., and VOGEL, S.N. (1992). Modulation of interferon consensus sequence binding protein mRNA in murine peritoneal macrophages. Induction by IFN-gamma and down-regulation by IFN-alpha, dexamethasone, and protein kinase inhibitors. J. Immunol. 148, 801807. source

      Not checked in the free run.

    • cites [10] 10. KANNO, Y., KOZAK, C.A., SCHINDLER, C., DRIGGERS, P.H., ENNIST, D.L., GLEASON, S.L., DARNELL, J.E., Jr., and OZATO, K. (1993). The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds. Mol. Cell. Biol. 13, 3951-3963. source

      Not checked in the free run.

    • cites [11] 11. POLITIS, A.D., OZATO, K., COLIGAN, J.E., and VOGEL, S.N. (1994). Regulation of IFN-gamma-induced nuclear expression of IFN consensus sequence binding protein in murine peritoneal macrophages. J. Immunol. 152, 2270-2278. source

      Not checked in the free run.

    • cites [12] 12. NELSON, N., KANNO, Y., HONG, C., CONTURSI, C., FUJITA, T., FOWLKES, B.J., O'CONNELL, E., HU-LI, J., PAUL, W.E., JANKOVIC, D., SHER, A.F., COLIGAN, J.E., THORNTON, A., APPELLA, E., YANG, Y., and OZATO, K. (1996). Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation. J. Immunol. 156, 3711-3720. source

      Not checked in the free run.

    • cites [13] 13. KANTAKAMALAKUL, W., POLITIS, A.D., MARECKI, S., SULLIVAN, T., OZATO, K., FENTON, M.J., and VOGEL, S.N. (1999). Regulation of IFN consensus sequence binding protein expression in murine macrophages. J. Immunol. 162, 7417-7425. source

      Not checked in the free run.

    • cites [15] 15. WANG, I.M., CONTURSI, C., MASUMI, A., MA, X., TRINCHIERI, G., and OZATO, K. (2000). An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271-279. source

      Not checked in the free run.

    • cites [34] 34. CONTURSI, C., WANG, I.M., GABRIELE, L., GADINA, M., O'SHEA, J., MORSE, H.C., 3rd, and OZATO, K. (2000). IFN consensus sequence binding protein potentiates Stat1-dependent activation of IFNgamma-responsive promoters in macrophages. Proc. Natl. Acad. Sci. USA 97, 91-96. source

      Not checked in the free run.

    • cites [2] 2. NGUYEN, H., HISCOTT, J., and PITHA, P.M. (1997). The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 8, 293-312. source

      Not checked in the free run.

    • cites [3] 3. TANIGUCHI, T., OGASAWARA, K., TAKAOKA, A., and TANAKA, N. (2001). IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623-655. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § TARGET DNA ELEMENTS, INTERACTING PROTEINS, AND REGULATION OF TRANSCRIPTION

    ICSBP associates with PU.1 and stimulates activity of the Ets/IRF composite element (EICE), which contains IRS and is present in immunoglobulin κ and λ, gp91phox, scavenger receptor, TLR-4, and IL-1β genes.

    “It also associates with PU.1 and stimulates activity of the Ets/IRF composite element (EICE), which also contains IRS and is present in the immunoglobulin (Ig) k and l , gp91 phox , scavenger receptor, toll-like receptor-4 (TLR-4), and interleukin (IL)-1 b genes. (5,23,26-30)”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [5] 5. MERARO, D., HASHMUELI, S., KOREN, B., AZRIEL, A., OUMARD, A., KIRCHHOFF, S., HAUSER, H., NAGULAPALLI, S., ATCHISON, M.L., and LEVI, B.-Z. (1999). Proteinprotein and DNA-protein interactions affect the activity of lymphoid-specific IFN regulatory factors. J. Immunol. 163, 64686478. source

      Not checked in the free run.

    • cites [23] 23. FUJII, Y., SHIMIZU, T., KUSUMOTO, M., KYOGOKU, Y., TANIGUCHI, T., and HAKOSHIMA, T. (1999). Crystal structure of an IRF-DNA complex reveals novel DNA recognition and cooperative binding to a tandem repeat of core sequences. EMBO J. 18, 5028-5041. source

      Not checked in the free run.

    • cites [26] 26. BRASS, A.L., ZHU, A.Q., and SINGH, H. (1999). Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J. 18, 977-991. source

      Not checked in the free run.

    • cites [27] 27. MARECKI, S., ATCHISON, M.L., and FENTON, M.J. (1999). Differential expression and distinct functions of IFN regulatory factor 4 and IFN consensus sequence binding protein in macrophages. J. Immunol. 163, 2713-2722. source

      Not checked in the free run.

    • cites [28] 28. EKLUND, E.A, JALAVA, A., and KAKAR, R. (1998). PU.1, interferon regulatory factor 1, and interferon consensus sequencebinding protein cooperate to increase gp91 (phox) expression. J. Biol. Chem. 273, 13957-13965. source

      Not checked in the free run.

    • cites [29] 29. REHLI, M., POLTORAK, A., SCHWARZFISCHER, L., KRAUSE, S.W., ANDREESEN, R., and BEUTLER, B. (2000). PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human toll-like receptor 4 gene. J. Biol. Chem. 275, 9773-9781. source

      Not checked in the free run.

    • cites [30] 30. MARECKI, S., RIENDEAU, C.J., LIANG, M.D., and FENTON, M.J. (2001). PU.1 and multiple IFN regulatory factor proteins synergize to mediate transcriptional activation of the human IL-1beta gene. J. Immunol. 166, 6829-6838. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ABSTRACT

    ICSBP-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome, where a systemic expansion of granulocytes is followed by a fatal blast crisis.

    “In addition, ICSBP 2 / 2 mice develop a chronic myelogenous leukemia (CML)-like syndrome, where a systemic expansion of granulocytes is followed by a fatal blast crisis.”
    • Also stated in: § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION · plain
      “Unexpectedly, ICSBP 2 / 2 mice were found to develop a syndrome resembling CML in humans. (37)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] 37. HOLTSCHKE, T., LOHLER, 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., 3rd, OZATO, K., and HORAK, I. (1996). Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307-317. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ABSTRACT

    ICSBP-/- mice harbor an increased number of myeloid progenitor cells, and the -/- progenitors preferentially give rise to granulocytes, although they cannot efficiently generate macrophages.

    “ICSBP 2 / 2 mice harbor an increased number of myeloid progenitor cells, and the 2 / 2 progenitors preferentially give rise to granulocytes, although they cannot efficiently generate another descendant of the myeloid lineage, macrophages.”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · plain
      “It was shown that adult bone marrow and fetal liver of ICSBP 2 / 2 mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte-macrop hage colony-stimulating factor (GM-CSF) and granulocyte colonystimulating factor (G-CSF) in vitro , as assessed by colony-forming assay. (49)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] 49. SCHELLER, M., FOERSTER, J., HEYWORTH, C.M., WARING, J.F., LOHLER, J., GILMORE, G.L., SHADDUCK, R.K., DEXTER, T.M., and HORAK, I. (1999). Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood 94, 3764-3771. source

      Not checked in the free run.

    • cites [54] 54. TAMURA, T., NAGAMURA-INOUE, T., SHMELTZER, Z., KUWATA, T., and OZATO, K. (2000). ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155-165. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP is expressed in hematopoietic cells, including monocyte/macrophage lineage, B lymphocytes, and activated T lymphocytes, and is inducible by IFN-γ in these cells.

    “ICSBP is expressed in the hematopoietic cells, including cells of the monocyte/macrophage lineage, B lymphocytes, and activated T lymphocytes, and is inducible by IFNg in these cells, suggesting its role in immune cells. (6,9-13)”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [6] 6. WEISZ, A., MARX, P., SHARF, R., APPELLA, E., DRIGGERS, P.H., OZATO, K., and LEVI, B.-Z. (1992). Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. J. Biol. Chem. 267, 25589-25596. source

      Not checked in the free run.

    • cites [9] 9. POLITIS, A.D., SIVO, J., DRIGGERS, P.H., OZATO, K., and VOGEL, S.N. (1992). Modulation of interferon consensus sequence binding protein mRNA in murine peritoneal macrophages. Induction by IFN-gamma and down-regulation by IFN-alpha, dexamethasone, and protein kinase inhibitors. J. Immunol. 148, 801807. source

      Not checked in the free run.

    • cites [10] 10. KANNO, Y., KOZAK, C.A., SCHINDLER, C., DRIGGERS, P.H., ENNIST, D.L., GLEASON, S.L., DARNELL, J.E., Jr., and OZATO, K. (1993). The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds. Mol. Cell. Biol. 13, 3951-3963. source

      Not checked in the free run.

    • cites [11] 11. POLITIS, A.D., OZATO, K., COLIGAN, J.E., and VOGEL, S.N. (1994). Regulation of IFN-gamma-induced nuclear expression of IFN consensus sequence binding protein in murine peritoneal macrophages. J. Immunol. 152, 2270-2278. source

      Not checked in the free run.

    • cites [12] 12. NELSON, N., KANNO, Y., HONG, C., CONTURSI, C., FUJITA, T., FOWLKES, B.J., O'CONNELL, E., HU-LI, J., PAUL, W.E., JANKOVIC, D., SHER, A.F., COLIGAN, J.E., THORNTON, A., APPELLA, E., YANG, Y., and OZATO, K. (1996). Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation. J. Immunol. 156, 3711-3720. source

      Not checked in the free run.

    • cites [13] 13. KANTAKAMALAKUL, W., POLITIS, A.D., MARECKI, S., SULLIVAN, T., OZATO, K., FENTON, M.J., and VOGEL, S.N. (1999). Regulation of IFN consensus sequence binding protein expression in murine macrophages. J. Immunol. 162, 7417-7425. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § TARGET DNA ELEMENTS, INTERACTING PROTEINS, AND REGULATION OF TRANSCRIPTION

    ICSBP interacts with IRF-1, IRF-2, or IRF-4 on the ISRE and negatively regulates some IFN-inducible genes, such as ISG15, which carries a functional ISRE.

    “ICSBP interacts with IRF-1, IRF2, or IRF-4 on the ISRE and negatively regulates some IFNinducible genes, such as ISG15 , which carries a functional ISRE. (4,24,25)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] 4. SHARF, R., AZRIEL, A., LEJBKOWICZ, F., WINOGRAD, S.S., EHRLICH, R., and LEVI, B.-Z. (1995). Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. J. Biol. Chem. 270, 13063-13069. source

      Not checked in the free run.

    • cites [24] 24. 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., et al. (1994). Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Proc. Natl. Acad. Sci. USA 91, 5046-5050. source

      Not checked in the free run.

    • cites [25] 25. ROSENBAUER, F., WARING, J.F., FOERSTER, J., WIETSTRUK, M., PHILIPP, D., and HORAK, I. (1999). Interferon consensus sequence binding protein and interferon regulatory factor4/Pip form a complex that represses the expression of the interferon-stimulated gene-15 in macrophages. Blood 94, 42744281. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Regulation of IL-12 p40 gene by ICSBP

    ICSBP-/- mice are deficient in producing IL-12 and IFN-γ and are unable to mount a Th1-mediated response.

    “ICSBP 2 / 2 mice were shown to be deficient in producing IL-12 and IFNg and were unable to mount a Th1-mediated response. (37,40,41)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] 37. HOLTSCHKE, T., LOHLER, 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., 3rd, OZATO, K., and HORAK, I. (1996). Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307-317. source

      Not checked in the free run.

    • cites [40] 40. GIESE, N.A., GABRIELE, L., DOHERTY, T.M., KLINMAN, D.M., TADESSE-HEATH, L., CONTURSI, C., EPSTEIN, S.L., and MORSE, H.C., 3rd (1997). Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535-1546. source

      Not checked in the free run.

    • cites [41] 41. SCHARTON-KERSTEN, T., CONTURSI, C., MASUMI, A., SHER, A., and OZATO, K. (1997). Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523-1534. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP was originally cloned as a nuclear protein that binds to IFN consensus sequence (ICS) in the major histocompatibility complex (MHC) class I genes.

    “I NTERFERON (IFN) CONSENSUS SEQUENCE BINDING (ICSBP), also designated IFN regulatory factor-8 (IRF-8), was originally cloned as a nuclear protein that binds to IFN consensus sequence (ICS) in the major histocompatibility complex (MHC) class I genes. (1)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] 1. DRIGGERS, P.H., ENNIST, D.L., GLEASON, S.L., MAK, W.H., MARKS, M.S., LEVI, B.Z., FLANAGAN, J.R., APPELLA, E., and OZATO, K. (1990). An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA 87, 3743-3747. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP belongs to the IRF transcription factor family, which includes nine mammalian members and four virally encoded homologs.

    “It belongs to the family of IRF transcription factors, which includes nine mammalian members and four virally encoded homologs. (2,3)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] 2. NGUYEN, H., HISCOTT, J., and PITHA, P.M. (1997). The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 8, 293-312. source

      Not checked in the free run.

    • cites [3] 3. TANIGUCHI, T., OGASAWARA, K., TAKAOKA, A., and TANAKA, N. (2001). IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623-655. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § PHOSPHORYLATION OF ICSBP

    ICSBP binds Trip15 (CSN2), a component of the COP9/signalosome (CSN) complex, and the CSN complex phosphorylates a serine residue within the IAD of ICSBP that is essential for efficient association with IRF-1.

    “ICSBP was shown to bind Trip15 (CSN2), which is a component of the COP9/signalosome (CSN) complex.”
    • Also stated in: § PHOSPHORYLATION OF ICSBP · plain
      “The CSN complex was able to phosphorylate a serine residue within the IAD of ICSBP, the residue of which phosphorylation is essential for efficient association with IRF-1. (36)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] 36. COHEN, H., AZRIEL, A., COHEN, T., MERARO, D., HASHMUELI, S., BECH-OTSCHIR, D., KRAFT, R., DUBIEL, W., and LEVI, B.-Z. (2000). 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. J. Biol. Chem. 275, 3908139089. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § TARGET DNA ELEMENTS, INTERACTING PROTEINS, AND REGULATION OF TRANSCRIPTION

    Interactions with IRF-1/2 and PU.1 significantly enhance DNA-binding activity of ICSBP and are mediated through the IAD.

    “Interactions with IRF-1/2 and PU.1 significantly enhance DNA-binding activity of ICSBP and are mediated through the IAD. (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 5. MERARO, D., HASHMUELI, S., KOREN, B., AZRIEL, A., OUMARD, A., KIRCHHOFF, S., HAUSER, H., NAGULAPALLI, S., ATCHISON, M.L., and LEVI, B.-Z. (1999). Proteinprotein and DNA-protein interactions affect the activity of lymphoid-specific IFN regulatory factors. J. Immunol. 163, 64686478. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ABSTRACT

    Studies with myeloid progenitor cells have shown that ICSBP drives their differentiation toward macrophage, whereas it inhibits granulocyte differentiation.

    “Studies with myeloid progenitor cells have shown that ICSBP drives their differentiation toward macrophage, whereas it inhibits granulocyte differentiation.”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · plain
      “Transduction of a retrovirus carrying the ICSBP gene caused marked differentiation in the progenitor cells, leading to generation of mature macrophages with phagocytic activity, which coincided with the induction of DNA-binding activity specific for ISRE and EICE (Fig. 3). (54)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] 54. TAMURA, T., NAGAMURA-INOUE, T., SHMELTZER, Z., KUWATA, T., and OZATO, K. (2000). ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155-165. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § PHOSPHORYLATION OF ICSBP

    Tyr phosphorylation negatively regulates ICSBP's own DNA binding activity, but is essential for formation of a heterodimer with IRF-1/2, and Tyr-phosphorylated ICSBP can bind target DNA only through association with IRF-1/2.

    “Although this Tyr phosphorylation negatively regulates ICSBP's own DNA binding activity, it is essential for the formation of heterodimer with IRF-1/2, and Tyr-phosphorylated ICSBP can bind target DNA only through association with IRF-1/2. (35)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. SHARF, R., MERARO, D., AZRIEL, A., THORNTON, A.M., OZATO, K., PETRICOIN, E.F., LARNER, A.C., SCHAPER, F., HAUSER, H., and LEVI, B.-Z. (1997). Phosphorylation events modulate the ability of interferon consensus sequence binding protein to interact with interferon regulatory factors and to bind DNA. J. Biol. Chem. 272, 9785-9792. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    ICSBP has a conserved DNA-binding domain (DBD) at the N-terminal region and an IRF association domain (IAD) in the C-terminal region.

    “ICSBP has the DNAbinding domain (DBD) conserved in the IRF family at the Nterminal region and the IRF association domain (IAD) in the C-terminal region (Fig. 1). (2-5)”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [2] 2. NGUYEN, H., HISCOTT, J., and PITHA, P.M. (1997). The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 8, 293-312. source

      Not checked in the free run.

    • cites [3] 3. TANIGUCHI, T., OGASAWARA, K., TAKAOKA, A., and TANAKA, N. (2001). IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623-655. source

      Not checked in the free run.

    • cites [4] 4. SHARF, R., AZRIEL, A., LEJBKOWICZ, F., WINOGRAD, S.S., EHRLICH, R., and LEVI, B.-Z. (1995). Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. J. Biol. Chem. 270, 13063-13069. source

      Not checked in the free run.

    • cites [5] 5. MERARO, D., HASHMUELI, S., KOREN, B., AZRIEL, A., OUMARD, A., KIRCHHOFF, S., HAUSER, H., NAGULAPALLI, S., ATCHISON, M.L., and LEVI, B.-Z. (1999). Proteinprotein and DNA-protein interactions affect the activity of lymphoid-specific IFN regulatory factors. J. Immunol. 163, 64686478. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § ABSTRACT

    The loss of ICSBP leads to immunodeficiency and CML-like syndrome, and ICSBP plays a critical role in the development of myeloid cells.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § CLONING, STRUCTURE, AND EXPRESSION OF ICSBP

    LPS also induces ICSBP, albeit to a lesser degree, and synergizes with IFN-γ in macrophages.

    “Lipopolysaccharide (LPS) also induces ICSBP, albeit to a lesser degree, and synergizes with IFNg in macrophages. (13-15)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] 13. KANTAKAMALAKUL, W., POLITIS, A.D., MARECKI, S., SULLIVAN, T., OZATO, K., FENTON, M.J., and VOGEL, S.N. (1999). Regulation of IFN consensus sequence binding protein expression in murine macrophages. J. Immunol. 162, 7417-7425. source

      Not checked in the free run.

    • cites [14] 14. BARBER, S.A., FULTZ, M.J., SALKOWSKI, C.A., and VOGEL, S.N. (1995). Differential expression of interferon regulatory factor 1 (IRF-1), IRF-2, and interferon consensus sequence binding protein genes in lipopolysaccharide (LPS)-responsive and LPS-hyporesponsive macrophages. Infect. Immun. 63, 601-608. source

      Not checked in the free run.

    • cites [15] 15. WANG, I.M., CONTURSI, C., MASUMI, A., MA, X., TRINCHIERI, G., and OZATO, K. (2000). An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271-279. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    ICSBP may play an important role in the pathogenesis of leukemia not only as an intrinsic regulator in the leukemic cells but also as an immune regulator.

    “ICSBP may play an important role in the pathogenesis of leukemia not only as an intrinsic regulator in the leukemic cells but also as an immune regulator.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § ICSBPretrovirus

    ICSBP potentiates activation of GAS in macrophages, and ICSBP-/- macrophages are defective in inducing some IFN-γ-responsive genes such as FcγRI and iNOS but are capable of activating Stat1 in response to IFN-γ.

    “A recent study suggests that ICSBP potentiates activation of GAS in macrophages. (34)”
    • Also stated in: § ICSBPretrovirus · plain
      “Macrophages from ICSBP 2 / 2 mice were found to be defective in inducing some IFNg -responsive genes, such as Fc g receptor I (Fc g RI) and nitric oxide synthase (iNOS) genes. However, they were capable of activating Stat1 in response to IFNg .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] 34. CONTURSI, C., WANG, I.M., GABRIELE, L., GADINA, M., O'SHEA, J., MORSE, H.C., 3rd, and OZATO, K. (2000). IFN consensus sequence binding protein potentiates Stat1-dependent activation of IFNgamma-responsive promoters in macrophages. Proc. Natl. Acad. Sci. USA 97, 91-96. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Regulation of myeloid cell growth and differentiation

    ICSBP stimulates expression of genes important for macrophage differentiation and represses a series of genes required for granulocyte differentiation, with the two events internally coupled through the action of ICSBP, indicating a critical role in lineage selection of myeloid progenitors.

    “These results suggest that whereas ICSBP stimulates expression of genes important for macrophage differentiation, it represses a series of genes required for granulocyte differentiation and that the two events are internally coupled through the action of ICSBP (Fig. 4).”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · hedged
      “The dual mode of ICSBP action indicates that it plays a critical role in the lineage selection of myeloid progenitor.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Transcriptional pathways regulated by ICSBP

    Egr-1 has been implicated in macrophage differentiation.

    “It is interesting to note that ICSBP induces a zinc finger transcription factor Egr-1 that has been implicated in macrophage differentiation, (57)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] 57. NGUYEN, H.Q., HOFFMAN, L.B., and LIEBERMANN, D.A. - (1993). The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell 72, 197-209. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    ICSBP regulates the proliferation and differentiation of hematopoietic cells and may act as a tumor suppressor.

    “Therefore, it was suggested that ICSBP regulates the proliferation and differentiation of hematopoietic cells and may act as a tumor suppressor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    ICSBP-/- mice develop a syndrome resembling CML in humans, with systemic expansion and infiltration of granulocytes causing lymphadenopathy and hepatosplenomegaly in essentially 100% of mice.

    “Unexpectedly, ICSBP 2 / 2 mice were found to develop a syndrome resembling CML in humans. (37)”
    • Also stated in: § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION · plain
      “The most significant alteration was a systemic expansion and infiltration of granulocytes (predominantly mature neutrophils), causing lymphadenopathy and hepatosplenomegaly, which was observed in essentially 100% of ICSBP 2 / 2 mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] 37. HOLTSCHKE, T., LOHLER, 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., 3rd, OZATO, K., and HORAK, I. (1996). Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307-317. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Regulation of myeloid cell growth and differentiation

    ICSBP-/- myeloid progenitor cell lines grow in a GM-CSF-dependent manner and differentiate into mature granulocytes in response to G-CSF; transduction of ICSBP causes marked differentiation into mature macrophages with phagocytic activity, represses granulocyte-specific genes, and inhibits G-CSF-mediated granulocyte growth and differentiation.

    “These progenitor cells grew in a GM-CSF-dependent manner and were capable of differentiating into mature granulocytes in response to G-CSF.”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · plain
      “Transduction of a retrovirus carrying the ICSBP gene caused marked differentiation in the progenitor cells, leading to generation of mature macrophages with phagocytic activity, which coincided with the induction of DNA-binding activity specific for ISRE and EICE (Fig. 3). (54)”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · plain
      “Furthermore, ICSBP inhibited G-CSF-mediated granulocyte growth and differentiation in the ICSBP 2 / 2 progenitor cells and in the 32Dcl.3 myeloid progenitor cell line. (54)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] 54. TAMURA, T., NAGAMURA-INOUE, T., SHMELTZER, Z., KUWATA, T., and OZATO, K. (2000). ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155-165. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Regulation of myeloid cell growth and differentiation

    Adult bone marrow and fetal liver of ICSBP-/- mice harbor increased numbers of progenitor cells that are hyperresponsive to GM-CSF and G-CSF in vitro, and their response to M-CSF is strongly reduced, with ICSBP-/- colonies formed in the presence of M-CSF being mostly granulocytes.

    “It was shown that adult bone marrow and fetal liver of ICSBP 2 / 2 mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte-macrop hage colony-stimulating factor (GM-CSF) and granulocyte colonystimulating factor (G-CSF) in vitro , as assessed by colony-forming assay. (49)”
    • Also stated in: § Regulation of myeloid cell growth and differentiation · boosted
      “In contrast, their response to macrophage colony-stimulating factor (M-CSF) was strongly reduced, and, surprisingly, ICSBP 2 / 2 colonies formed in the presence of M-CSF were mostly granulocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] 49. SCHELLER, M., FOERSTER, J., HEYWORTH, C.M., WARING, J.F., LOHLER, J., GILMORE, G.L., SHADDUCK, R.K., DEXTER, T.M., and HORAK, I. (1999). Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood 94, 3764-3771. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    IFN-α, the effective cytokine for therapy of CML, induced ICSBP expression in vivo, and ICSBP expression correlated with pretreatment risk features and cytogenetic response to IFN-α in CML.

    “IFNa , the effective cytokine for therapy of CML, induced ICSBP expression in vivo , and the ICSBP expression correlated with pretreatment risk features and cytogenetic response to IFNa in CML. (51)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] 51. SCHMIDT, M., HOCHHAUS, A., NITSCHE, A., HEHLMANN, R., and NEUBAUER, A. (2001). 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. Blood 97, 3648-3650. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    Forced expression of ICSBP induces potent immunity against Bcr-Abl-induced leukemia in mice, and in vivo leukemia caused by transformed BaF3 cells was completely inhibited by coexpression of ICSBP.

    “Furthermore, it was shown that forced expression of ICSBP induces potent immunity against Bcr-Abl-induced leukemia in mice. (53)”
    • Also stated in: § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION · plain
      “Although ectopic expression of ICSBP did not alter in vitro growth of Bcr-Abl-transformed BaF3 cells, in vivo leukemia caused by the transformed BaF3 was completely inhibited by coexpression of ICSBP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] 53. DENG, M., and DALEY, G.Q. (2001). Expression of interferon consensus sequence binding protein induces potent immunity against Bcr/Abl-induced leukemia. Blood 97, 3491-3497. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § ROLE OF ICSBP IN MYELOID CELL DIFFERENTIATION

    In the mouse model with a CML-like disease induced by Bcr-Abl, ICSBP expression was downregulated, and the mouse disease was ameliorated by coexpression of ICSBP.

    “In the mouse model with a CML-like disease induced by Bcr-Abl, ICSBP expression was also downregulated. Interestingly, the mouse disease was ameliorated by coexpression of ICSBP. (52)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] 52. HAO, S.X., and REN, R. (2000). Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in BcrAbl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder. Mol. Cell. Biol. 20, 1149-1161. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Regulation of IL-12 p40 gene by ICSBP

    ICSBP alone is able to activate mouse and human IL-12 p40 promoters, acting through the Ets site, and exogenous IRF-1 synergizes with ICSBP.

    “It was shown that ICSBP alone is able to activate mouse and human IL-12 p40 promoters.”
    • Also stated in: § Regulation of IL-12 p40 gene by ICSBP · hedged
      “Analysis of human IL-12 p40 promoter indicated that ICSBP acts through the Ets site, known to be important for activation by IFNg /LPS. (15)”
    • Also stated in: § Regulation of IL-12 p40 gene by ICSBP · plain
      “Although exogenous IRF-1, also shown to be necessary for IL-12 p40 gene expression, (45,46) had no effect on its own, it synergized with ICSBP.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] 15. WANG, I.M., CONTURSI, C., MASUMI, A., MA, X., TRINCHIERI, G., and OZATO, K. (2000). An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271-279. source

      Not checked in the free run.

    • cites [45] 45. TAKI, S., SATO, T., OGASAWARA, K., FUKUDA, T., SATO, M., HIDA, S., SUZUKI, G., MITSUYAMA, M., SHIN, E.H., KOJIMA, S., TANIGUCHI, T., and ASANO, Y. (1997). Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6, 673-679. source

      Not checked in the free run.

    • cites [46] 46. SALKOWSKI, C.A., KOPYDLOWSKI, K., BLANCO, J., CODY, M.J., McNALLY, R., and VOGEL, S.N. (1999). IL-12 is dysreg- - ulated in macrophages from IRF-1 and IRF-2 knockout mice. J. Immunol. 163, 1529-1536. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Regulation of IL-12 p40 gene by ICSBP

    ICSBP-/- macrophages or cells from draining lymph nodes are severely impaired in both basal and induced expression of the IL-12 p40 gene after infection, and a similar impairment occurs in peritoneal macrophages in response to various in vitro stimuli.

    “Strikingly, ICSBP 2 / 2 macrophages or cells from draining lymph nodes were severely impaired in both basal and induced expression of the IL-12 p40 gene after infection. (40,41)”
    • Also stated in: § Regulation of IL-12 p40 gene by ICSBP · plain
      “A similar impairment was noted for peritoneal macrophages in response to various in vitro stimuli, such as LPS, Staphylococcus aureus Cowan strain 1 (SAC), or soluble tachyzoite antigen (STAg) from T. gondii with and without IFNg pretreatment. (40,41)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] 40. GIESE, N.A., GABRIELE, L., DOHERTY, T.M., KLINMAN, D.M., TADESSE-HEATH, L., CONTURSI, C., EPSTEIN, S.L., and MORSE, H.C., 3rd (1997). Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535-1546. source

      Not checked in the free run.

    • cites [41] 41. SCHARTON-KERSTEN, T., CONTURSI, C., MASUMI, A., SHER, A., and OZATO, K. (1997). Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523-1534. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Regulation of IL-12 p40 gene by ICSBP

    ICSBP regulates IL-12 p40 gene activation and, as a consequence, promotes IFN-γ-dependent host resistance.

    “It is apparent that ICSBP regulates IL-12 p40 gene activation and, as a consequence, promotes IFNg -dependent host resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Regulation of IL-12 p40 gene by ICSBP

    IL-12 is composed of the p35 and p40 subunits, forming a heterodimer p70.

    “IL-12 is composed of the p35 and p40 subunits, forming a heterodimer p70. (42)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] 42. TRINCHIERI, G. (1998). Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv. Immunol. 70, 83-243. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning
    § Transcriptional pathways regulated by ICSBP

    ICSBP may act upstream of Egr-1, and once Egr-1 is induced by ICSBP it may generate a secondary cascade of gene expression emanating from Egr-1.

    “ICSBP may act upstream of Egr-1, and once Egr-1 is induced by ICSBP, it may generate a secondary cascade of gene expression emanating from Egr-1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Transcriptional pathways regulated by ICSBP

    ICSBP directs myeloid progenitor cells to differentiate into macrophages and facilitates their functional maturation.

    “It directs them to differentiate into macrophages and facilitates their functional maturation while it inhibits growth and differentiation of granulocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Transcriptional pathways regulated by ICSBP

    ICSBP interacts with IRF-1 and IRF-2 and antagonizes IRF-1 activation of promoters through the standard ISRE.

    “ICSBP also interacts with IRF-1 and IRF-2 and antagonizes IRF-1 activation of promoters through the standard ISRE.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [15] 15. WANG, I.M., CONTURSI, C., MASUMI, A., MA, X., TRINCHIERI, G., and OZATO, K. (2000). An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271-279. source

      Not checked in the free run.

    • cites [28] 28. EKLUND, E.A, JALAVA, A., and KAKAR, R. (1998). PU.1, interferon regulatory factor 1, and interferon consensus sequencebinding protein cooperate to increase gp91 (phox) expression. J. Biol. Chem. 273, 13957-13965. source

      Not checked in the free run.

    • cites [30] 30. MARECKI, S., RIENDEAU, C.J., LIANG, M.D., and FENTON, M.J. (2001). PU.1 and multiple IFN regulatory factor proteins synergize to mediate transcriptional activation of the human IL-1beta gene. J. Immunol. 166, 6829-6838. source

      Not checked in the free run.

    • cites [48] 48. EKLUND, E.A., and KAKAR, R. (1999). Recruitment of CREBbinding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gammainduced p67 phox and gp91 phox expression. J. Immunol. 163, 60956105. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Transcriptional pathways regulated by ICSBP

    IRF-1 has anti-oncogenic and proapoptotic functions.

    “in light of well-known anti-oncogenic and proapoptotic functions of IRF1 and the oncogenic potential of IRF-2, (61)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 61. TANAKA, N., and TANIGUCHI, T. (2000). The interferon regulatory factors and oncogenesis. Semin. Cancer Biol. 10, 73-81. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Transcriptional pathways regulated by ICSBP

    ICSBP expression profoundly affects various disease processes ranging from infections to leukemia.

    “Its expression profoundly affects various disease processes ranging from infections to leukemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § Transcriptional pathways regulated by ICSBP

    ICSBP inhibits growth and differentiation of granulocytes.

    “It directs them to differentiate into macrophages and facilitates their functional maturation while it inhibits growth and differentiation of granulocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Transcriptional pathways regulated by ICSBP

    ICSBP is an IRF member dedicated to the growth and differentiation of myeloid cells and to the functional activation of macrophages.

    “In conclusion, ICSBP is an IRF member dedicated to the growth and differentiation of myeloid cells and functional activation of macrophages.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Transcriptional pathways regulated by ICSBP

    IRF-2 has oncogenic potential.

    “in light of well-known anti-oncogenic and proapoptotic functions of IRF1 and the oncogenic potential of IRF-2, (61)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 61. TANAKA, N., and TANIGUCHI, T. (2000). The interferon regulatory factors and oncogenesis. Semin. Cancer Biol. 10, 73-81. source

      Not checked in the free run.

46 of 46

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Cites

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Research works printed but not linked: 1

  1. LI W., 1999, Invest. Ophthalmol. Vis. Sci., 40, 976

Cited by

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Related

Authors
Tamura, T., & Ozato, K.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Journal of Interferon & Cytokine Research
Publisher
SAGE Publications
Published
2002-01
Volume
22
Issue
1
Pages
145-152
ISSN
  • 1079-9907 (ISSN-L)
  • 1557-7465
DOI
10.1089/107999002753452755
OpenAlex
W160560928
Semantic Scholar
6497a15c5667a6e90a4e65ae79472ef8ed2cfa77
Cited by
183
References
72
Citations by year
2025: 2 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 3 · 2017: 12 · 2016: 6 · 2015: 6 · 2014: 13 · 2013: 7 · 2012: 7
FWCI
1.04
Type
journal article
Language
en
Open access
closed
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Journal of Interferon & Cytokine Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Keywords
interferon regulatory factors, myeloid cell development, macrophage differentiation, granulocytic differentiation, myeloid progenitor cells, immunodeficiency, apoptosis resistance
MeSH terms
Interferon Regulatory Factor-8, Animals, Cell Differentiation, Gene Expression Regulation, Humans, Phosphorylation, Repressor Proteins, Transcription Factors, Transcription, Genetic, Trans-Activators, Consensus Sequence, Apoptosis, Mice, Knockout, Myeloid Cells, Interferon Regulatory Factors, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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