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B Signaling Regulates Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG via Intronic Binding Sequences1
* Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
The Jackson Laboratory, Bar Harbor, ME 04609; and
Department of Genome Science, University of Cincinnati College of Medicine, Cincinnati, OH 45237
The neonatal Fc receptor for IgG (FcRn) functions to transport maternal IgG to a fetus or newborn and to protect IgG from degradation. Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown. Stimulation of intestinal epithelial cell lines, macrophage-like THP-1, and freshly isolated human monocytes with the cytokine TNF-
rapidly up-regulated FcRn gene expression. In addition, the TLR ligands LPS and CpG oligodeoxynucleotide enhanced the level of FcRn expression in THP-1 and monocytes. Treatment of TNF-stimulated THP-1 cells with the NF-
B-specific inhibitor or overexpression of a dominant negative mutant inhibitory NF-B (IB; S32A/S36A) resulted in down-regulation of FcRn expression. By using chromatin immunoprecipitation we identified three NF-B binding sequences within introns 2 and 4 of the human FcRn gene. An EMSA confirmed the p50/p50 and/or p65/p50 complex (s) bound to intron 2- or 4-derived oligonucleotides containing putative NF-B binding sequences, respectively. The intronic NF-B sequences in combination with the promoter or alone regulated the expression of a luciferase reporter gene in response to TNF- stimulation or overexpression of NF-B p65 and p50. DNA looping interactions potentially occurred after the stimulation between intronic NF-B sequences and the FcRn promoter as shown by a chromosome conformation capture assay. Finally, TNF- stimulations enhanced IgG transport across an intestinal Caco-2 epithelial monolayer. Together, these data provide the first evidence that NF-B signaling via intronic sequences regulates FcRn expression and function.
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 in part supported by the faculty start-up package and Maryland Agricultural Experiment Station competitive grants from the University of Maryland (to X.Z.), National Institutes of Health Grants AI67965 and AI65892 (to X.Z.) and DK56597, and a grant from The Alliance for Lupus Research (to D.C.R.).
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; β2m, β2-microglobulin; CAPE, caffeic acid phenethyl ester; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; 3C, chromosome conformation capture.
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  X. Liu, L. Ye, Y. Bai, H. Mojidi, N. E. Simister, and X. Zhu Activation of the JAK/STAT-1 Signaling Pathway by IFN-{gamma} Can Down-Regulate Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG J. Immunol., July 1, 2008; 181(1): 449 - 463. [Abstract] [Full Text] [PDF]
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