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Chain Gene Induced by GM-CSF Β Receptor Regulation of Human High-Affinity Ige Molecular Mechanisms for Transcriptional

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Chain Gene Induced by GM-CSF Β Receptor Regulation of Human High-Affinity Ige Molecular Mechanisms for Transcriptional Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF This information is current as Kyoko Takahashi, Natsuko Hayashi, Shuichi Kaminogawa of September 23, 2021. and Chisei Ra J Immunol 2006; 177:4605-4611; ; doi: 10.4049/jimmunol.177.7.4605 http://www.jimmunol.org/content/177/7/4605 Downloaded from References This article cites 39 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/177/7/4605.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 23, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor ␤-Chain Gene Induced by GM-CSF1 Kyoko Takahashi,*† Natsuko Hayashi,*‡ Shuichi Kaminogawa,† and Chisei Ra2* The ␤-chain of the high-affinity receptor for IgE (Fc␧RI) plays an important role in regulating activation of Fc␧RI-expressing cells such as mast cells in allergic reactions. We already reported that the transcription factor myeloid zinc finger (MZF) 1 which formed a high m.w. complex including four and a half LIM-only protein (FHL)3 in the nucleus repressed human ␤-chain gene expression through an element in the fourth intron. We also found that GM-CSF induced expression of MZF-1 and nuclear translocation of FHL3. We screened a human cDNA library and identified NFY which was reported to bind histone deacetylases (HDACs) as a constituent of the complex. The C-subunit of NFY was demonstrated to form a ternary complex with MZF-1/FHL3 Downloaded from and interact with a ␤-chain gene region including the element in the fourth intron. HDAC1 and HDAC2 were also shown to interact with the fourth intron region of the ␤-chain gene. In a human mast cell line HMC-1 cultured with GM-CSF, both ␤-chain expression and acetylation of histones interacting with the fourth intron region of the ␤-chain gene were decreased. Collectively, these results indicated that HDACs, which were recruited to the ␤-chain gene through the element in the fourth intron by MZF-1/FHL3/NFY, repressed ␤-chain gene transcription by deacetylation of histones in the presence of GM-CSF. These mech- ␤ anisms will be involved in not only the cell type-specific repression of -chain gene expression in differentiating hemopoietic cells http://www.jimmunol.org/ but also the repression of ␤-chain gene expression in the peripheral cells under specific circumstances. The Journal of Immu- nology, 2006, 177: 4605–4611. ells of limited types such as mast cells, basophils, eosin- to the stimulation by allergens. Recently, it was revealed that ophils (1), monocytes (2), Langerhans cells (3, 4), plate- ␤-chain amplified degranulation and leukotriene secretion but sup- C lets (5, 6), and neutrophils (7) express the high-affinity pressed cytokine production (12), indicating that ␤-chain regulates receptor for IgE (Fc␧RI). Fc␧RI plays an important role in trig- distinct intracellular signaling events in both positive and negative gering IgE-mediated allergic reaction. Cross-linking of Fc␧RI on manners by the same molecule of itself. Furthermore, an alterna- effector cells, for example mast cells, by Ag (allergen)-IgE com- tive splice variant which encoded only an N-terminal portion of by guest on September 23, 2021 plexes triggers allergic reaction by activating intracellular signal ␤-chain was found to be expressed in human mast cells (13). This cascades to induce not only the release of chemical mediators in truncation variant competed with full-length ␤ and prevented the early-phase reaction but also cytokine gene expressions leading Fc␧RI surface expression by inhibiting ␣-chain maturation (13). ␧ to the late-phase reaction. Moreover, Fc RI on epidermal Langer- Because all of these findings indicate that ␤-chain is a fine regu- hans cells in the skin is known to be involved in the Ag presen- lator of Fc␧RI-mediated cell activation to precisely control the tation by facilitating uptake of IgE-associated allergens, suggesting allergic reaction, elucidation of regulatory mechanisms of ␤-chain its pivotal role in the pathophysiology of atopic dermatitis. expression will make a meaningful contribution to medical inter- Fc␧RI is composed of three different subunits, ␣, ␤, and ␥,of vention for allergy. In addition, because ␤-chain has only been which the ␣-chain directly binds IgE through its extracellular do- ␥ ␧ main, while the ␤- and ␥-chains are responsible for mediating in- reported to associate with Fc RIIIA except for Fc RI (14) and its tracellular signals. Although a functional receptor is expressed expression is limited in the specific types of cells such as mast cells ␣␤␥ ␣␥ and basophils, applications which are targeted for ␤-chain are ex- both as tetramers ( 2) and trimers ( 2) in humans (8), intra- cellular signals (9, 10), in addition to cell surface expression of the pected to exert cell type-specific effects. ␧ ␤ receptor (11), were reported to be significantly amplified by The genomic structure of the human Fc RI -chain gene was ␤-chain, indicating that ␤-chain increases cell activation sensitivity already determined (15), however, only a few analyses were per- formed on regulatory mechanisms of ␤-chain gene transcription. Two Oct-1-binding sites in the 5Ј untranslated region were essen- *Division of Molecular Cell Immunology and Allergology, Advanced Medical Re- search Center, Nihon University Graduate School of Medical Sciences, Tokyo, Japan; tial for activation of ␤-chain gene promoter (16). We revealed that †Nihon University College of Bioresource Sciences, Kanagawa, Japan; and ‡Depart- the transcription factor myeloid zinc finger (MZF)3 1 repressed ment of Applied Biological Chemistry, Tamagawa University, Tokyo, Japan ␤-chain gene expression through an element in the fourth intron Received for publication March 15, 2006. Accepted for publication July 14, 2006. (17). It was suggested that this transcriptional repression required 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 a cofactor; we therefore screened for MZF-1-binding proteins and with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported in part by a Grant-in Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 2 Address correspondence and reprint requests to Dr. Chisei Ra, Division of Molec- 3 Abbreviations used in this paper: MZF, myeloid zinc finger; FHL, four and a half ular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon LIM-only protein; HDAC, histone deacetylase; BD, binding domain; ADH, alcohol University Graduate School of Medical Sciences, 30-1 Oyaguchi Kamimachi, dehydrogenase; HA, hemagglutinin; AD, activation domain; ChIP, chromatin Itabashi-ku, Tokyo 173-8610, Japan. E-mail address: [email protected] immunoprecipitation. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4606 REGULATION OF HUMAN FC␧RI ␤-CHAIN GENE EXPRESSION identified a four and a half LIM-only protein (FHL)3 as a repres- growing colonies were transferred onto SD-Trp/-Leu/-His/-Met/-Ade(ad- sive cofactor (18). FHL3 was predicted to act as an adaptor mol- enine) plates containing X-␣-Gal to select those expressing the other re- ␣ ecule recruiting unidentified other molecules to the MZF-1/DNA porter genes of ADE2 and MEL1.X- -Gal was purchased from BD Clon- tech. Furthermore, to obtain proteins interacting with MZF-1 not complex, because MZF-1 and FHL3 formed a very large m.w. independent of FHL3 but dependent on FHL3, the cells which grew on the complex in the nucleus (18). In contrast, GM-CSF was reported to medium without methionine but hardly grew on the medium including induce MZF-1 expression (19). Moreover, we found that GM-CSF methionine were selected. pACT2 plasmids carrying cDNA inserts were induced translocation of FHL3 from the cytoplasm to the nucleus rescued from the selected clones and their nucleotide sequences were de- termined. The interaction among MZF-1, FHL3, and the candidate protein (18), suggesting that both up-regulation of MZF-1 and nuclear NFYC was retested by cotransformation of AH109 cells with pBridge- translocation of FHL3 by GM-CSF facilitate formation of the MZF-1/FHL3 and pACT2-NFYC. The cells were examined for expression MZF-1/FHL3 complex in the nucleus and reduce ␤-chain gene of HIS3 and ADE2 reporter genes by testing their ability to grow on -His/- expression through the element in the fourth intron. It was actually Ade medium in the absence (FHL3 was expressed) and presence (FHL3 reported that GM-CSF decreased Fc␧RI expression on the surface was not expressed) of methionine. of a human mast cell line HMC-1 (20, 21). In this study, we report Immunoprecipitation of in vitro-translated MZF-1, FHL3, that Fc␧RI ␤-chain gene expression can be suppressed in the pres- and NFY ence of GM-CSF through deacetylation of histones mediated by histone deacetylases (HDACs) which are recruited to the ␤-chain c-Myc-tagged MZF-1 (aa 1–217), FHL3, and HA-tagged NFYC were pro- duced by in vitro transcription/translation method with TNT T7 Quick Cou- gene through the complex including MZF-1/FHL3.
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