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I-Related Neonatal Fc Receptor for Igg This Information Is Current As of September 26, 2021

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I-Related Neonatal Fc Receptor for Igg This Information Is Current As of September 26, 2021 Activation of the JAK/STAT-1 Signaling Pathway by IFN- γ Can Down-Regulate Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG This information is current as of September 26, 2021. Xindong Liu, Lilin Ye, Yu Bai, Habi Mojidi, Neil E. Simister and Xiaoping Zhu J Immunol 2008; 181:449-463; ; doi: 10.4049/jimmunol.181.1.449 http://www.jimmunol.org/content/181/1/449 Downloaded from References This article cites 74 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/181/1/449.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 26, 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 Activation of the JAK/STAT-1 Signaling Pathway by IFN-␥ Can Down-Regulate Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG1 Xindong Liu,* Lilin Ye,* Yu Bai,* Habi Mojidi,*† Neil E. Simister,‡ and Xiaoping Zhu2*† Expression of many MHC genes is enhanced at the transcriptional or posttranscriptional level following exposure to the cytokine IFN-␥. However, in this study we found that IFN-␥ down-regulated the constitutive expression of the neonatal Fc receptor (FcRn), an MHC class I-related molecule that functions to transport maternal IgG and protect IgG and albumin from degradation. Epithelial cell, macrophage-like THP-1 cell, and freshly isolated human PBMC exposure to IFN-␥ resulted in a significant decrease of FcRn expression as assessed by real-time RT-PCR and Western blotting. The down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. Chromatin immunoprecipitation and gel mobility shift assays showed that STAT-1 Downloaded from bound to an IFN-␥ activation site in the human FcRn promoter region. Luciferase expression from an FcRn promoter-luciferase reporter gene construct was not altered in JAK1- and STAT-1-deficient cells following exposure to IFN-␥, whereas expression of JAK1 or STAT-1 protein restored the IFN-␥ inhibitory effect on luciferase activity. The repressive effect of IFN-␥ on the FcRn promoter was selectively reversed or blocked by mutations of the core nucleotides in the IFN-␥ activation site sequence and by over- expression of the STAT-1 inhibitor PIAS1 or the dominant negative phospho-STAT-1 mutations at Tyr-701 and/or Ser-727 residues. Furthermore, STAT-1 might down-regulate FcRn transcription through sequestering the transcriptional coactivator CREB binding http://www.jimmunol.org/ protein/p300. Functionally, IFN-␥ stimulation dampened bidirectional transport of IgG across a polarized Calu-3 lung epithelial mono- layer. Taken together, our results indicate that the JAK/STAT-1 signaling pathway was necessary and sufficient to mediate the down- regulation of FcRn gene expression by IFN-␥. The Journal of Immunology, 2008, 181: 449–463. he neonatal Fc receptor (FcRn)3 for IgG was first char- the maternal to the fetal/newborn blood in placental and/or intes- acterized in the intestinal epithelial cells of neonatal ro- tinal tissues (8, 9). FcRn, therefore, plays a major role in the pass- T dents; however, its expression has recently been identified ing on maternal immunity to newborns, possibly in all mammals. in a variety of cell types and tissues including epithelial cells, FcRn also functions in the maintenance of IgG and albumin ho- endothelial cells, macrophages, and dendritic cells in rodents and meostasis by salvaging either of them from degradation (8, 10, 11). by guest on September 26, 2021 humans of all ages (1–4). The structure of FcRn is similar to that In the model proposed by Brambell et al., IgG is taken into cells by of MHC class I Ags, being composed of a heavy chain (45 kDa in pinocytosis or endocytosis from the surrounding tissue fluid or humans and 50 kDa in rodents) that is noncovalently attached to a blood (12). FcRn in acidic compartments, such as the endosome, ␤ light chain 2-microglobulin (12 kDa) (5, 6). However, FcRn is binds and recycles IgG out of the cell to avoid IgG degradation in not capable of presenting Ags to T cells because its Ag binding the lysosome (8, 12). In fact, FcRn displays pH-dependent binding groove is too narrow (7). Despite this, FcRn is identified as a of IgG or albumin; specifically, FcRn preferentially binds IgG or transport receptor involved in mediating the transfer of IgG from albumin at acidic pH (6–6.5) and releases IgG or albumin at neu- tral pH (7–7.4) (8, 11, 12). The transport and protective properties for IgG by FcRn are fully supported by several studies in which *Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary ␤ Medicine, and †Maryland Pathogen Research Institute, Graduate Program in Molec- mice deficient in either 2-microglobulin or FcRn heavy chain ular and Cell Biology, University of Maryland, College Park, MD 20742; and ‡Rosen- exhibit either failure of transport of maternal IgG or significant stiel Center for Basic Biomedical Sciences and Biology Department, Brandeis Uni- reduction in the serum half-life of IgG (3, 10, 13, 14). Recently, versity, Waltham, MA 02254 FcRn is also shown to play a role in phagocytosis (15). Received for publication February 19, 2008. Accepted for publication April 25, 2008. IFNs are multifunctional cytokines that have antiviral, antipro- 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 liferative, antitumor, and immunomodulatory effects (16, 17). In with 18 U.S.C. Section 1734 solely to indicate this fact. the case of IFN-␥, the cell membrane receptor for IFN-␥ is com- 1 This work was supported in part by National Institutes of Health Grants AI67965, posed of two subunits, IFN-␥R1 and IFN-␥R2. Upon binding to AI65892, and AI73139 (to X.Z.), a faculty start-up package (to X.Z.), and MAES IFN-␥, the IFN-␥ receptor rapidly associates with the Janus ty- competitive grants (to X.Z.) from University of Maryland. Y.B. is in part supported by a fellowship from China Scholarship Council. rosine kinases JAK1 and JAK2. JAK enzymes phosphorylate one ␥ 2 Address correspondence and reprint requests to Dr. Xiaoping Zhu, Virginia-Mary- another and then subsequently phosphorylate the IFN- receptor, land Regional College of Veterinary Medicine, University of Maryland, 8075 Green- which results in the formation of a docking site for the latent cy- mead Drive, College Park, MD 20742. E-mail address: [email protected] toplasmic transcription factor named STAT-1, a member of the 3 Abbreviations used in this paper: FcRn, neonatal Fc receptor; CBP, CREB binding STAT (signal transducer and activator of transcription) protein protein; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; GAS, DAPI, 4Ј,6Ј-diamidino-2-phenylindole; Ii, invariant chain; IFN-␥ activation site; IRF, IFN family (18). Upon phosphorylation, STAT-1 homodimerizes, regulatory factor; ISRE, IFN-stimulated response element; MMP, matrix metallopro- translocates to the nucleus, and regulates gene transcription by teinase; PIAS1, protein inhibitor of activated; SR-A, scavenger receptor A; STAT-1; binding to IFN-␥-activated sequences (GAS) in the IFN-␥-induc- poly(dI-dC), poly(deoxyinosinic-deoxycytidylic acid). ible genes. Homodimerization of STAT-1 is mediated by the bind- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 ing of the phosphorylated tyrosine 701 of one STAT-1 monomer to www.jimmunol.org 450 DOWN-REGULATION OF FcRn GENE TRANSCRIPTION BY IFN-␥ the Src homology 2 domain of another. However, maximal tran- extension. PCR products were resolved on 1.5% agarose gels and visual- scriptional activity by active STAT-1 homodimers also requires ized by staining with ethidium bromide. Integrated density values for the STAT-1 phosphorylation at serine 727 (19–21). It has been found FcRn binds were normalized to the GAPDH values to yield a semiquan- titative assessment. that STAT-1 phosphorylation plays a critical role in IFN-mediated The freshly isolated human PBMCs (106 cells/ml) were stimulated with innate immunity to microbial infection (22). STAT-1 signaling can IFN-␥ (25 ng/ml) for 24 h. The total RNA samples were extracted. The also be negatively regulated by the protein inhibitor of activated RNA (400 ng/reaction) was reverse transcribed to yield first-strand cDNA STAT-1 (PIAS1) and suppressor of cytokine signaling (SOCS) using SuperScript III (Invitrogen). Real-time RT-PCR was performed us- ␥ ing FcRn and GAPDH primers (34) and the SYBR Green Supermix kit (23). More interestingly, IFN- can also regulate expression of its (Bio-Rad Laboratories) in a Chromo 4 thermocycler (MJ Research). FcRn inducible genes in a STAT-1-independent manner (24–27), sug- expression was calculated following normalization to GAPDH levels by gesting that multiple signaling pathways in parallel play important the comparative ⌬⌬ threshold cycle method. All reactions were performed roles in the biological response to IFN-␥. for 40 cycles: 15 s at 94 °C, 15 s at 58 °C, and 20 s at 72 °C. The specificity The pivotal roles in the protection and transport of IgG have led of the amplification reactions was confirmed by melt curve analysis.
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