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5045.Full.Pdf IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development This information is current as Maja Milanovic, Grzegorz Terszowski, Daniela Struck, of September 28, 2021. Oliver Liesenfeld and Dirk Carstanjen J Immunol 2008; 181:5045-5053; ; doi: 10.4049/jimmunol.181.7.5045 http://www.jimmunol.org/content/181/7/5045 Downloaded from References This article cites 47 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/181/7/5045.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development1 Maja Milanovic,2* Grzegorz Terszowski,2† Daniela Struck,2‡ Oliver Liesenfeld,‡ and Dirk Carstanjen3* IFN consensus sequence binding protein (Icsbp) (IFN response factor-8) is a hematopoietic transcription factor with dual functions in myelopoiesis and immunity. In this study, we report a novel role of Icsbp in regulating the development of eosinophils. Loss of Icsbp in mice leads to a reduction of eosinophils in different tissues. During parasite infection with the nematode Nippostrongylus brasiliensis, Icsbp-deficient mice fail to mount eosinophilia despite a vigorous IL-5 response. Numbers of phenotypically defined eosinophil progenitors are decreased and those progenitors have, on a per-cell basis, reduced eosinophil differentiation potential. The transcription factor Gata1, crucial for eosinophil development, is reduced expressed in committed eosinophil progenitors in wells as mature eosinophils. These findings identify Icsbp as a novel transcription factor critical for the development of the Downloaded from eosinophil lineage. The Journal of Immunology, 2008, 181: 5045–5053. osinophils, synonymous to eosinophil granulocytes, ac- Icsbp and Irf4 interact with Pu.1, another important hematopoietic count only for a minute fraction of leukocytes (around transcription factor for the development of eosinophils on a spe- E 1–3% in humans and mice) in the peripheral blood. Eo- cific DNA (EICE) sequence (15, 16). sinophils are involved in the immunity against parasite infections Targeted deletion of Icsbp in mice results in an increased sus- http://www.jimmunol.org/ and play a major role in the pathology of diverse allergic diseases ceptibility toward certain viruses (17), intracellular bacteria (18), (1–4). The most common cause of eosinophilia in humans world- and parasites (19). Moreover, loss of Icsbp in mice leads to a wide is helminthic infection. Contrasting the knowledge about eo- myeloproliferative syndrome characterized by accumulation and sinophils in different diseases, little is known about the ontogeny expansion of mature neutrophil granulocytes and myeloid progen- of eosinophils, their precursors and maturation steps and the mo- itor cells at the expense of monocytes and macrophages. This de- lecular control of eosinophil lineage commitment. The recent de- fect has been localized to the committed granulocyte-monocyte- scription of an eosinophil lineage-committed progenitor helps to progenitor (GMP) (20), but the molecular mechanisms underlying further elucidate eosinophil development (5). At the molecular the aberrant myeloid development are not understood today. by guest on September 28, 2021 level, several studies have implicated Gata1 (6, 7), and the C/EBP We noted a reduction of eosinophils in the peripheral blood and family, notably ␣ (8), ␤ (9), and ␧ (10, 11) as critical transcrip- bone marrow in Icsbp-deficient mice. In this study, we provide tional regulators of transcripts encoding typical proteins of the eo- sinophil as well as the formation of mature eosinophils. insight into the cellular and molecular basis for this defect in eo- Icsbp, IFN consensus sequence binding protein,4 synonymous to sinophil numbers. To this end, we have examined the development Irf8 (IFN response factor-8) is an IFN-␥-induced transcription fac- of eosinophils in Icsbp-deficient mice under normal and parasite- tor that regulates IFN responsive genes (12–14). In contrast to infected conditions. We observed that Icsbp is a critical transcrip- most other members of the Irf-family, Icsbp is preferentially ex- tion factor for the regulation of the development of eosinophils pressed in the hematopoietic system. Proteins of the Irf-family under physiological but especially under pathological conditions. bind to the IFN-stimulated response element and control genes Challenged with the parasite Nippostrongylus brasiliensis, Icsbp- harboring this element within their promoters (14). Furthermore, deficient mice fail to develop eosinophilia. This is due to an ab- normal developmental potential of the eosinophil progenitor (EoP) in the absence of Icsbp. *Leibniz-Forschungsinstitut fuer Molekulare Pharmakologie, Berlin, Germany; †De- partment for Immunology, University of Ulm, Ulm, Germany; and ‡Institute for Mi- crobiology and Hygiene, Charite´, Benjamin Franklin University Hospital, Berlin, Germany Materials and Methods Received for publication September 27, 2007. Accepted for publication July 30, 2008. Animals and parasites The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance Icsbp-deficient mice and wild-type littermates (background C57BL/6 and with 18 U.S.C. Section 1734 solely to indicate this fact. C57BL/6 ϫ 129Sv) have been previously described (17). Mice were bred 1 This work was supported by the Deutsche Forschungsgemeinschaft to D.C. (CA and maintained under specific pathogen-free conditions in the Forschung- 306/1–1) and to G.T. (SFB 497). seinrichtung fu¨r Experimentelle Medizin der Charite´, Universitaetsmedizin 2 M.M., G.T., and D.S. have contributed equally to this work. Berlin, Campus Benjamin Franklin. Sex- and age-matched mice were 8 to 3 16 wk of age when used. Each experiment was repeated at least three times Address correspondence and reprint requests to Dr. Dirk Carstanjen, Leibniz-For- unless otherwise indicated. A mouse-adapted strain of N. brasiliensis was schungsinstitut fuer Molekulare Pharmakologie, Krahmer Strasse 6, D-12207 Berlin, Germany. E-mail address: [email protected] maintained and passed in Lewis rats at the Zentrum fu¨r Infektionsfors- chung, Universita¨t Wuerzburg, Wuerzburg, Germany (Dr. Klaus Erb). Fe- 4 Abbreviations used in this paper: Icsbp, IFN consensus sequence binding protein; Irf8, IFN response factor-8; GMP, granulocyte-monocyte-progenitor; EoP, eosinophil ces were collected from stock rats and served as a source of L3 after ␤ ␤ incubation of the fecal slurry. In brief 750 L3 larvae were injected s.c. to progenitor; EP, erythroid progenitor; c, common -chain. establish infection. All animal experiments were approved by the local Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 authorities according to the German Federal Animal Protection Act. www.jimmunol.org 5046 Icsbp AND EOSINOPHIL DEVELOPMENT FIGURE 1. Reduced numbers of eosino- phils among bone marrow and peritoneal ex- udate cells in Icsbp-deficient mice. Percent- ages of eosinophils in the bone marrow (A) and eosinophil and neutrophil granulocytes in peritoneal exudates (B) were determined by morphological criteria following May- Gruenwald-Giemsa staining of freshly iso- lated bone marrow or peritoneal exudate cells. Total of 500 cells were analyzed per mouse. Statistical significance of differences between Icsbp ϩ/ϩ (Ⅺ) and Ϫ/Ϫ (f) mice are indicated above the bars (n ϭ 4 untreated and n ϭ 7 thioglycollate). Downloaded from http://www.jimmunol.org/ Histopathology spins were prepared, stained with May-Gruenwald-Giemsa, and differen- tially counted. Lavage cells were harvested, plastic adherent cells were Mice were anesthetized with isofluorane inhalation and bled by cardiac depleted, and remaining cells were stained with FITC-labeled F4/80 (Se- puncture at 13 days after infection. Their small intestines were fixed in a rotec), PE-labeled CCR3 (R&D Systems), and allophycocyanin-labeled solution containing 10% formalin, 70% ethanol, and 5% acetic acid. Sec- CD11b (clone M1/70, BD Biosciences) conjugated Abs. Cells were sorted tions of small intestines were stained with H&E. Numbers of goblet cells on a MoFlow Cytometer (Cytomation) and eosinophils were isolated. Sample in the small intestine were determined microscopically in two randomly cytospins of sorted cells were prepared and stained with May-Gruenwald- chosen areas of two villi in at least three mice per experimental group. Giemsa. For induction of apoptosis, purified eosinophils were plated in IMDM (PAA) supplemented with 10% FCS (Biochrom),
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