NF-κB Signaling Regulates Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG via Intronic Binding Sequences

Abstract

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-α 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-κB-specific inhibitor or overexpression of a dominant negative mutant inhibitory NF-κB (IκBα; S32A/S36A) resulted in down-regulation of FcRn expression. By using chromatin immunoprecipitation we identified three NF-κB 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-κB binding sequences, respectively. The intronic NF-κB sequences in combination with the promoter or alone regulated the expression of a luciferase reporter gene in response to TNF-α stimulation or overexpression of NF-κB p65 and p50. DNA looping interactions potentially occurred after the stimulation between intronic NF-κB sequences and the FcRn promoter as shown by a chromosome conformation capture assay. Finally, TNF-α stimulations enhanced IgG transport across an intestinal Caco-2 epithelial monolayer. Together, these data provide the first evidence that NF-κB signaling via intronic sequences regulates FcRn expression and function.

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

“…Moreover, hypercatabolism of IgG has been observed in mice with lupus-like syndrome, by disease-induced impairment of FcRn function (41). FcRn expression in intestinal epithelial cells, macrophage-like THP-1, and primary human monocytes can be induced by inflammatory markers such as TNF-α and IL-1β (42). Additionally, biodistribution studies with FcRn knockout animals have reported altered PK and distribution of IgG.…”

Identification and characterization of an alternatively spliced variant of the MHC class I-related porcine neonatal Fc receptor for IgG

“…Third, the expression of the splicing variants is highly regulated by inflammatory cytokines during inflammation, i.e., production of splicing variants of MHC class I molecules can be induced by proinflammatory cytokines [46,47]. Our recent data showed that FcRn expression can be regulated by cytokines such as TNF-α and IL-1β [48]. Taking this into account, it would be interesting to know whether proinflammatory cytokines also regulate or change the patterns of FcRn splicing.…”

Potential of HMEC-1 Line and HUVEC Primary Culture Cells to Study the Neonatal IgG Fc Receptor <i>in vitro</i>

“…Another explanation is differential gene regulation. In this regard, Liu et al (2007) found that stimulation of intestinal epithelial cell lines, macrophage-like THP-1 and freshly isolated human monocytes with TNF-α up-regulated FcRn gene expression. In addition, the TLR ligands LPS and CpG oligodeoxynucleotide enhanced FcRn expression, specifically in THP-1 and monocytes.…”

“…The FcRn thus seems widely distributed in the human body. It is constitutively expressed, is up-regulated by TNF-α and LPS and down-regulated by IFN-γ (Liu et al, 2007;.…”