Abstract
Human epithelial, endothelial and PMA-differentiated THP-1 cell lines were used as model systems to study the transcriptional regulation of the human FCGRT gene encoding the alpha chain of hFcRn. The data obtained from site-directed mutagenesis in transient transfection experiments indicate that the Sp1 sites at positions -641, -635, and -313, CF1/YY1 elements at positions -586 and -357, and the AP-1 motif at -276 within the-660/-233 fragment of the human FCGRT promoter (hFCGRT) participate in the regulation of human FCGRT in all selected cell lines. However, their individual contribution to promoter activity is not equivalent. The Sp1 binding site at -313 and the AP-1 site at -276 are critical for the activity of the hFCGRT promoter in epithelial and endothelial cells. Moreover, the CF1/YY1 site at -586 in differentiated THP-1 cells, plays an essential role in the transcriptional activity of the promoter. In addition, the C/EBPbeta binding site at -497 of the hFCGRT promoter in epithelial and endothelial cells, and the C/EBPbeta motif located at -497 and -233 within the hFCGRT promoter in differentiated THP-1 cells may function as positive regulatory sequences in response to LPS or PMA stimulation. EMSA and supershift analyses showed that the functionally identified binding motifs in the hFCGRT promoter were able to specifically interact with their corresponding (Sp1, Sp2, Sp3, c-Fos, c-Jun, YY1, and C/EBPbeta or C/EBPdelta) transcription factors (TFs), suggesting their possible involvement in the regulation of the human FCGRT gene expression.
Highlights
The neonatal Fc receptor, FcRn, was originally identified as a receptor responsible for the IgG binding to the intestinal epithelium and fetal yolk sack of neonatal rats and mice [1,2,3]
HFcRn was previously reported to be expressed in THP-1 cells [14] and the human intestinal Caco-2 cell line [31], the presence of the human FCGRT mRNA was verified in the selected Caco-2, Lu 106, human umbilical vein endothelial cell line (HUVEC), human skin microvascular endothelial cell line (HSkMEC), and THP-1 cell lines by Reverse transcription (RT)-PCR to make sure that these cells are a suitable model systems for studying transcriptional regulation of human FCGRT
The control normal rabbit IgG (Fig 6A, lane 7) exerted no effect. These results indicate that the heterodimeric transcription factors C/EBPβ and C/EBPδ of the C/EBP family participate in specific interactions with the C/EBPβ binding site at position -497 within the human FCGRT promoter (hFCGRT) promoter
Summary
The neonatal Fc receptor, FcRn, was originally identified as a receptor responsible for the IgG binding to the intestinal epithelium and fetal yolk sack of neonatal rats and mice [1,2,3]. The hFcRn receptor is structurally related to the MHC class I proteins and consists of transmembrane α-chain (45 kDa) in noncovalent association with β2-microglobulin (light chain, 12 kDa) [16]. PLOS ONE | DOI:10.1371/journal.pone.0135141 August 7, 2015
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