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Downloaded From Cooperation Among Stat1, Glucocorticoid Receptor, and PU.1 in Transcriptional Activation of the High-Affinity Fcγ Receptor I in Monocytes This information is current as of September 27, 2021. Saara Aittomäki, Marko Pesu, Bernd Groner, Olli A. Jänne, Jorma J. Palvimo and Olli Silvennoinen J Immunol 2000; 164:5689-5697; ; doi: 10.4049/jimmunol.164.11.5689 http://www.jimmunol.org/content/164/11/5689 Downloaded from References This article cites 51 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/164/11/5689.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 27, 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 © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cooperation Among Stat1, Glucocorticoid Receptor, and PU.1 in Transcriptional Activation of the High-Affinity Fc␥ Receptor I in Monocytes1 Saara Aittoma¨ki,* Marko Pesu,*† Bernd Groner,‡ Olli A. Ja¨nne,§ Jorma J. Palvimo,§ and Olli Silvennoinen2*† IFN-␥ and glucocorticoids regulate inflammatory and immune responses through Stat1 and glucocorticoid receptor (GR) tran- scription factors, respectively. The biological responses to these polypeptides are determined by integration of various signaling pathways in a cell-type and promoter-dependent manner. In this study we have characterized the molecular basis for the func- tional cooperation between IFN-␥ and dexamethasone (Dex) in the induction of the high-affinity Fc␥ receptor I (Fc␥RI) in monocytes. Dex did not affect IFN-␥-induced Stat1 DNA binding activity or induce novel DNA-binding complexes to the Fc␥RI Downloaded from promoter. By using cell systems lacking functional GR or Stat1, we showed that GR stimulated Stat1-dependent transcription in a ligand-dependent manner, while Stat1 did not influence GR-dependent transcription. The cooperation required phosphorylation of Tyr701, DNA binding, and the trans-activation domain of Stat1, but did not involve Ser727 phosphorylation of Stat1 or physical interaction between GR and Stat1. The costimulatory effect of Dex was not dependent on a consensus glucocorticoid response element in the Stat1-responsive promoters, but required the DNA-binding and trans-activation functions of GR, and Dex-induced protein synthesis. GR activated the natural Fc␥RI promoter construct, and this response required both Stat1 and the Ets family http://www.jimmunol.org/ transcription factor PU.1. Previously, physical association between GR and Stat5 has been shown to enhance Stat5-dependent and suppress GR-dependent transcription. The results shown here demonstrate a distinct, indirect mechanism of cross-modulation between cytokine and steroid receptor signaling that integrates Stat1 and GR pathways with cell type-specific PU.1 transcription factor in the regulation of Fc␥RI gene transcription. The Journal of Immunology, 2000, 164: 5689–5697. onocytes and their terminally differentiated counter- tional activation of monocytes and modulation of cytokine pro- parts, macrophages, carry out a variety of functions in duction (4–7). the first-line defense against foreign invaders such as In recent years the molecular mechanisms for IFN-␥ signal M by guest on September 27, 2021 phagocytosis and microbicidal activity against intracellular and ex- transduction have been elucidated (8, 9). IFN-␥ binds to a receptor tracellular microbes. Monocytes also serve as APC and critical complex consisting of IFN-␥RI and the accessory chain IFN-␥RII. activators of specific immune responses. During the immune re- Ligand-induced dimerization of the receptor chains results in ac- sponse, activated T cells provide a reciprocal activation stimulus to tivation of Jak1 and Jak2 tyrosine kinases and phosphorylation of monocytes by secretion of cytokines such as IFN-␥, one of the the IFN-␥RI on specific tyrosine residues that serve as docking most potent monocyte-activating agents (1). An important conse- sites for the Src homology 2 (SH2) domain of the latent cytoplas- quence of IFN-␥ stimulation in monocytes is up-regulated expres- mic transcription factor Stat1. In the receptor complex Stat1 be- sion of the high-affinity receptor for IgG (Fc␥RI, CD64) (2). Fc␥RI comes tyrosine phosphorylated and forms dimers that are translo- is a 72-kDa glycoprotein expressed predominantly on monocytes. cated to the nucleus and bind cognate promoter DNA sequences, It plays an important role in endocytosis of immune complexes and referred to as IFN-␥-activated site (GAS)3 (8). The Stat1 signaling opsonized microbes and in Ab-mediated cytotoxic reactions (3). pathway is essential for induction of the Fc␥RI gene, and Stat1- Engagement of the Fc␥RI promotes cellular signal transduction deficient mice are unresponsive to IFN-␥-induced Fc␥RI expres- through Src family and Syk tyrosine kinases and results in func- sion (10). Characterization of the Fc␥RI promoter has shown that the IFN-␥ regulatory region and regions determining myeloid cell- specific expression are conferred by two cis-elements within 190 nucleotides upstream of the translation initiation site. The IFN-␥- *Institute of Medical Technology, and Department of Medical Biochemistry, Uni- inducible region is localized to an IFN-␥ response region (GRR), † versity of Tampere, and Department of Clinical Microbiology, Tampere University which contains a GAS-like Stat1 binding element (11, 12). The Hospital, Tampere, Finland; ‡Chemotherapeutisches Forschungsinstitut, Georg Speyer Haus, Frankfurt am Main, Germany; and §Institute of Biomedicine, Depart- cell type-specific expression requires a downstream myeloid cell- ments of Physiology and Clinical Chemistry, University of Helsinki, Helsinki, activating transcription element, which binds the Ets family tran- Finland scription factor PU.1/Spi-1 (12, 13). Received for publication October 14, 1999. Accepted for publication March 22, 2000. 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 with 18 U.S.C. Section 1734 solely to indicate this fact. 3 Abbreviations used in this paper: GAS, IFN-␥-activated site; AF, activation function 1 This work was supported by the Academy of Finland, the Sigrid Juselius Founda- domain; CREB, cAMP response element binding protein; CBP, CREB binding pro- tion, and the Medical Research Fund of Tampere University Hospital. tein; IRF, IFN regulatory factor; CHX, cycloheximide; DBD, DNA binding domain; 2 Address correspondence and reprint requests to Dr. Olli Silvennoinen, Department Epo, erythropoietin; EpoR, Epo receptor; Fc␥RI, Fc receptor I for IgG; GR, glucocor- of Medical Biochemistry, University of Tampere, Lenkkeilijankatu 6, FIN-33014 ticoid receptor; GRE, glucocorticoid response element; GRR, IFN-␥ response region; Tampere, Finland. E-mail address: olli.silvennoinen@uta.fi Dex, dexamethasone; RLU, relative luciferase unit; TK, thymidine kinase. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 5690 GLUCOCORTICOID RECEPTOR REGULATES STAT1-MEDIATED TRANSCRIPTION Glucocorticoids have profound immunomodulatory effects. They Cell culture and transfection assays are widely used as immunosuppressive and anti-inflammatory agents HepG2, COS-7, and RAW264.7 cells (from American Type Culture Col- in autoimmune and allergic inflammatory diseases (14). Glucocorti- lection, Manassas, VA) were cultured in DMEM plus 10% FCS, and coids modulate the growth, differentiation, and function of lympho- THP-1 cells (from American Type Culture Collection) were cultured in cytes, neutrophils, eosinophils, mast cells, endothelial cells, and RPMI 1640 medium plus 10% FCS, all from Life Technologies/BRL (Gaithersburg, MD). U3A cells, provided by Dr. I. Kerr, were grown in monocytes through activation of the glucocorticoid receptor (GR) DMEM plus 10% Cosmic calf serum (HyClone, Logan, UT) (42). Human (15). GR belongs to the nuclear hormone receptor superfamily and peripheral blood monocytes were isolated from leukocyte-enriched buffy functions as a ligand-induced transcription factor. In unstimulated coats using Optiprep (Nycomed Pharma, Norway) density gradient cen- cells, GR exists in the cytoplasm in a complex with heat shock pro- trifugation according to the manufacturer’s instructions. After centrifuga- teins and immunophilins, and ligand binding dissociates the complex tion monocytes were collected from the low density cell fraction and washed twice with medium. The monocyte fraction was analyzed with and promotes nuclear transfer of GR. In the nucleus, GR homodimers forward and side scatter and for CD64 expression using FACScan. The bind to cognate DNA motifs known as glucocorticoid response ele- fraction contained ϳ60% monocytes; the rest of the cells were other mono- ments (GREs). GR displays both stimulatory
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