LDL immune complexes stimulate LDL receptor expression in U937 histiocytes via extracellular signal-regulated kinase and AP-1.
We have previously shown that LDL-containing immune complexes (LDL-ICs) induce up-regulation of LDL receptor (LDLR) expression in human macrophages. The present study further investigated the molecular mechanisms leading to LDLR up-regulation by LDL-ICs as well as the signaling pathways involved. Results showed that treatment of U937 histiocytes with LDL-ICs did not increase the precursors and the cleaved forms of sterol-regulatory element binding proteins (SREBPs) 1a and 2, suggesting that SREBPs may not be involved in LDLR up-regulation by LDL-ICs. Promoter deletion and mutation studies showed that the AP-1 binding sites were essential for LDL-IC-stimulated LDLR expression. Electrophoretic mobility shift assays further demonstrated that LDL-ICs stimulated transcription factor AP-1 activity. Studies assessing the signaling pathways involved in LDLR up-regulation by LDL-ICs showed that the up-regulation of LDLR was extracellular signal-regulated kinase (ERK) dependent. In conclusion, the present study shows that LDL-ICs up-regulate LDLR expression via the ERK signaling pathway and the AP-1 motif-dependent transcriptional activation.
Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, USA.
Yuchang
Y
Fu
Yan
Y
Huang
Sumita
S
Bandyopadhyay
Gabriel
G
Virella
Maria F
MF
Lopes-Virella
D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008957:Models, Genetic; D016296:Mutagenesis; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D020298:U937 Cells; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases