| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Can Down-Regulate Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG1
* Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, and
Maryland Pathogen Research Institute, Graduate Program in Molecular and Cell Biology, University of Maryland, College Park, MD 20742; and
Rosenstiel Center for Basic Biomedical Sciences and Biology Department, Brandeis University, Waltham, MA 02254
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 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 overexpression 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 protein/p300. Functionally, IFN- stimulation dampened bidirectional transport of IgG across a polarized Calu-3 lung epithelial monolayer. 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 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.
1 This work was supported in part by National Institutes of Health Grants AI67965, AI65892, and AI73139 (to X.Z.), a faculty start-up package (to X.Z.), and MAES competitive grants (to X.Z.) from University of Maryland. Y.B. is in part supported by a fellowship from China Scholarship Council.
2 Address correspondence and reprint requests to Dr. Xiaoping Zhu, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742. E-mail address: xzhu1{at}umd.edu
3 Abbreviations used in this paper: FcRn, neonatal Fc receptor; CBP, CREB binding protein; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; GAS, DAPI, 4',6'-diamidino-2-phenylindole; Ii, invariant chain; IFN- activation site; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; MMP, matrix metalloproteinase; PIAS1, protein inhibitor of activated; SR-A, scavenger receptor A; STAT-1; poly(dI-dC), poly(deoxyinosinic-deoxycytidylic acid).
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
