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Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes: Modulation of Interferon-Regulated Gene Expression by Rel/Nuclear Factor ␬B

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Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes: Modulation of Interferon-Regulated Gene Expression by Rel/Nuclear Factor ␬B Published April 10, 2000 Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes: Modulation of Interferon-regulated Gene Expression by Rel/Nuclear Factor ␬B By Raelene J. Grumont and Steve Gerondakis From The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia Abstract In lymphocytes, the Rel transcription factor is essential in establishing a pattern of gene expres- sion that promotes cell proliferation, survival, and differentiation. Here we show that mitogen- Downloaded from induced expression of interferon (IFN) regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a repressor of IFN-induced gene expression, the absence of IRF-4 expression in c-relϪրϪ B cells coincided with a greater sensitivity of these cells to the antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4 transgene restored IFN modulated c-relϪրϪ B cell proliferation to that of wild-type cells. This cross-regulation between two different signal- ing pathways represents a novel mechanism that Rel/nuclear factor ␬B can repress the tran- jem.rupress.org scription of IFN-regulated genes in a cell type–specific manner. Key words: Rel/NF-␬B • lymphocytes • IRF-4 • interferon • transcription Introduction During antigen and mitogen stimulation of lymphocytes, expression by binding to specific decameric sequences (␬B on June 3, 2015 specific genetic programs are established by the coordinated elements) located within the transcriptional regulatory re- activation of various signal transduction pathways, which in gions of cellular genes, particularly those encoding proteins turn, lead to morphologic changes, cell division, differenti- involved in immune, acute phase, and inflammatory re- ation, and the acquisition of immunological function. The sponses (3, 4). The five mammalian Rel/NF-␬B subunits temporal patterns of gene expression that underlie these share a conserved NH2-terminal domain (Rel homology processes in lymphocytes collectively span a time frame that domain [RHD]) that encompass sequences essential for extends from minutes to days, with the induction of imme- DNA binding, dimerization, and nuclear localization (3). diate early and early response genes coinciding with that The 50- and 52-kD forms of NF-␬B1 and NF-␬B2, re- period of mitogenic stimulation required to commit a cell spectively, comprise the RHD and lack intrinsic transcrip- to a program of activation (1). tional transactivating properties, whereas Rel, RelA, and One group of transcription factors essential for lympho- RelB all possess transactivation domains within their diver- cyte activation and immune function is the Rel/nuclear gent COOH termini (3). In most cell types, the majority of factor (NF)1-␬B proteins (2), homodimers and hetero- Rel/NF-␬B is sequestered as an inactive cytoplasmic com- dimers composed of related subunits that are encoded by a plex with inhibitor or I␬B proteins (5, 6). Diverse stimuli small multigene family. Rel/NF-␬B proteins regulate gene promote the nuclear translocation of cytoplasmic Rel/NF- ␬B by activating an I␬B kinase complex (for a review, see Address correspondence to Steve Gerondakis, The Walter and Eliza Hall reference 2) that phosphorylates conserved serine residues Institute of Medical Research, Post Office, The Royal Melbourne Hospi- on the I␬B proteins, targeting them for ubiquitin-depen- tal, Parkville, Victoria 3050, Australia. Phone: 61-39-345-2542; Fax: 61- dent proteosome-mediated degradation (5, 6). 39-347-0852; E-mail: [email protected] Rel is dispensable for normal embryonic development 1Abbreviations used in this paper: CAT, chloramphenicol acetyltrans- and hemopoiesis, but is essential for the division, survival, ferase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; IRF, IFN regulatory factor; ISRE, IFN stimulation differentiation, and immune function of mature lympho- response element; NF, nuclear factor; OAS, oligoadenylate synthetase; cytes and macrophages (7–11). To date, most of the genes RHD, Rel homology domain; RP, radioprotective. known to be direct transcriptional targets of Rel encode 1281 J. Exp. Med. The Rockefeller University Press • 0022-1007/2000/04/1281/11 $5.00 Volume 191, Number 8, April 17, 2000 1281–1291 http://www.jem.org/cgi/current/full/191/8/1281 Published April 10, 2000 cytokines, cytokine receptors, and immune-regulatory acetyltransferase (CAT), IRF4 H3-CAT, and IRF4 Sph1-CAT molecules such as IL-2, IL-3, GM-CSF, IL-6, TNF-␣, IL- consisted of the 2644-bp Pst1–Avr1, 1195-bp Hind3–Avr1, and 2R␣, and inducible nitric oxide synthase (iNOS [2, 3]). 498-bp Sph1–Avr1 genomic fragments, respectively, from the However, impaired expression of these proteins only partly murine IRF-4 5Ј flanking sequence inserted upstream of CAT in explains the immune defects exhibited by c-relϪրϪ mice. For the promoterless reporter plasmid pBCAT3 (22). IRF4 ␬B1m- CAT and IRF4 ␬B2m-CAT are derivatives of IRF4 Pst1-CAT, example, the B cell proliferative defect resulting from the in which NF-␬B binding sites ␬B1 (5Ј-GGGGATCCAC-3Ј at absence of Rel is due to a cell cycle block and enhanced Ϫ1733 to Ϫ1724) and ␬B2 (5Ј-GGGATCCCCC-3Ј at Ϫ686 to apoptosis (10). This impaired mitogenic response is a result Ϫ657) were altered by in vitro mutagenesis (23) to 5Ј-GGT- of the combined failure to induce the expression of prosur- CATAAAC-3Ј and 5Ј-GTCATCAACC-3Ј, respectively, or in vival genes such as A1 (11), and Rel-regulated genes neces- the case of IRF4 ␬B1m/␬B2m-CAT, where both sites have been sary for G1 progression, the latter of which remain to be mutated. The reporter plasmid pA3luc-ISRE comprising four identified. copies of the ISRE consensus sequence 5Ј-GTACCAGTTTCG- As part of a strategy aimed at identifying genes regulated GTTTCCCTTG-3Ј inserted upstream of the minimal mouse by Rel, the expression of genes normally induced early in H2Dk promoter in the reporter plasmid pGem-luc (Promega) lymphocyte activation were examined in c-relϪրϪ B and T was provided by H. Thomas (Walter and Eliza Hall Institute for cells. Among those surveyed, IFN regulatory factor 4 (IRF-4), Medical Research). The expression plasmid pCMDIRF-4 was generated by inserting a 2-kb Xba1–Hind3 murine IRF-4 cDNA a lymphoid-restricted member of the IFN family of tran- encompassing the entire IRF-4 coding region into pCMD-8. A scription factors, emerged as a promising candidate. IRF-4 cDNA encompassing the murine IRF-4 coding region fused in expression is rapidly induced in resting lymphocytes by mi- frame with an NH2-terminal FLAG tag was cloned as a BglII– Downloaded from togens (12) with kinetics that closely follow the nuclear in- EcoR1 insert into the retroviral expression vector pMSCV- duction of Rel (13). Like Rel, it also appears to be critical IRES–green fluorescent protein (GFP) (a gift of Dr. L. Van Par- in lymphocyte proliferation, as IRF-4ϪրϪ B and T cells re- ijs, California Institute of Technology, Pasadena, CA). spond poorly to mitogens (14) and deregulated overexpres- Purification of Primary B and T Lymphocytes. Small resting B sion of IRF-4 due to the translocation of the gene into the and T lymphocytes were purified from the spleens of 6–8-wk-old ϪրϪ ϪրϪ Ig CH locus occurs in a subset of human multiple myelo- wild-type, nfkb1 , and c-rel mice by negative sorting (10) ® PLUS™ mas (15). Proteins comprising the IRF family, of which on a FACS or FACStar cell sorter (Becton Dickinson). The purity of all sorted B and T lymphocytes was verified by jem.rupress.org there are at least 10 members, function either as transcrip- staining a portion of the cells with PE-labeled anti-B220 or anti- tional activators or repressors (16). All share a conserved Thy1 antibodies, respectively (Caltag Labs) and ranged between NH2-terminal domain required for the recognition and 95 and 99%. binding of a specific DNA consensus sequence, the IFN Cell Culture and Lymphocyte Activation in Tissue Culture. The stimulation response element (ISRE) found in the promot- Jurkat T cell line was maintained in RPMI 1640 supplemented ers of IFN-regulated genes (17, 18). Although originally with 8% FCS, and 293T fibroblasts were grown in DMEM/8% identified as mediating the diverse biological activities of FCS. The B cell lines 404.1 and B1.1 have been described previ- on June 3, 2015 type I and type II IFNs (19, 20), subsequent studies have ously (11) and were cultured in DMEM/10% FCS/50 ␮M BME. revealed roles for IRFs that are independent of IFN signal- Primary B and T lymphocytes were cultured in the high glucose ing. These include controlling susceptibility to oncogenic version of DMEM supplemented with 13 mM folic acid, 250 transformation, promoting cell cycle progression, and the mM l-asparagine, 50 ␮M 2-ME, and 10% FCS. Spleen cells were cultured at an initial concentration of 106 cells/ml, and induction of growth arrest and programmed cell death (18). FACS®-purified B or T lymphocytes were cultured at an input Here we show that IRF-4, a repressor of ISRE-mediated concentration of 3 ϫ 105 cells/ml. All primary B or T cells were transcription, while normally rapidly upregulated in mito- stimulated in vitro with LPS (Difco), affinity-purified goat anti– gen stimulated B and T cells is not induced in activated mouse IgM (FabЈ) fragment (Jackson ImmunoResearch Labora- c-relϪրϪ lymphocytes. This impaired expression of IRF-4, tories), rat anti–mouse radioprotective (RP) mAbs (24), Con A which coincides with a hyperresponsiveness of c-relϪրϪ lym- (Amersham Pharmacia Biotech), PMA and ionomycin (Sigma phocytes to type I and type II IFNs and enhanced expres- Chemical Co.), or plate-coated mouse anti-CD3 and anti-CD28 sion of certain IFN-induced genes, establishes a novel mAbs as described previously (11).
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