NF-kappaB signaling regulates functional expression of the MHC class I-related neonatal Fc receptor for IgG via intronic binding sequences.
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-alpha 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-kappaB-specific inhibitor or overexpression of a dominant negative mutant inhibitory NF-kappaB (IkappaBalpha; S32A/S36A) resulted in down-regulation of FcRn expression. By using chromatin immunoprecipitation we identified three NF-kappaB 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-kappaB binding sequences, respectively. The intronic NF-kappaB sequences in combination with the promoter or alone regulated the expression of a luciferase reporter gene in response to TNF-alpha stimulation or overexpression of NF-kappaB p65 and p50. DNA looping interactions potentially occurred after the stimulation between intronic NF-kappaB sequences and the FcRn promoter as shown by a chromosome conformation capture assay. Finally, TNF-alpha stimulations enhanced IgG transport across an intestinal Caco-2 epithelial monolayer. Together, these data provide the first evidence that NF-kappaB signaling via intronic sequences regulates FcRn expression and function.
Liu
Xindong
X
Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742, USA.
Ye
Lilin
L
Christianson
Gregory J
GJ
Yang
Jun-Qi
JQ
Roopenian
Derry C
DC
Zhu
Xiaoping
X
D001483:Base Sequence; D001665:Binding Sites; D018938:Caco-2 Cells; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology; D007438:Introns; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011961:Receptors, Fc / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D016328:NF-kappa B; D011961:Receptors, Fc; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; C100688:Fc receptor, neonatal
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