Early growth response-1 is involved in foam cell formation and is upregulated by the TLR9-MyD88-ERK1/2 pathway.
Early growth response-1 (Egr-1), a zinc finger transcription factor, plays a key regulatory role in pathological cardiovascular processes including atherosclerosis. Here, we investigate whether Egr-1 expression and foam cell formation require toll-like receptor 9 (TLR9) and myeloid differentiation factor 88 (MyD88). CpG DNA and its related synthetic CpG oligodeoxynucleotides (CpG ODN) play an important role in immunity and inflammation. CpG ODN increased expression of Egr-1 and formation of foam cells in Raw264.7 cells or bone marrow-derived macrophages. Egr-1 siRNA decreased foam cell formation by CpG ODN compared to that of control siRNA. In addition, when TLR9 or MyD88 was knocked down, CpG ODN-induced Egr-1 expression was also attenuated. CpG ODN increased ERK1/2 phosphorylation. U0126, a MEK pathway inhibitor, suppressed activation of Egr-1 expression by CpG ODN. CpG ODN-induced expression of tissue factor (TF) and NGFI-A binding protein 2 (Nab2), and the expression of both genes is blocked by knockdown of TLR9 or MyD88 siRNA or MEK inhibition. These results suggest that CpG ODN activates the TLR9-MyD88-ERK1/2 pathway causing expression of Egr-1 and its target genes such as TF and Nab2, thus inducing foam cell formation.
Kim
Jin-Sik
JS
Aging-Associated Vascular Disease Research Center, Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717, South Korea.
Park
Dae-Weon
DW
Lee
Hyung-Kyoung
HK
Kim
Jae-Ryong
JR
Baek
Suk-Hwan
SH
D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology*; D005487:Foam Cells / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D013925:Thromboplastin / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D015854:Up-Regulation
C408982:CPG-oligonucleotide; D051766:Early Growth Response Protein 1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C099945:Nab2 protein, mouse; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D012097:Repressor Proteins; D051217:Toll-Like Receptor 9; D013925:Thromboplastin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3