Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation

► IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. ► Nuclear IL-33 increased the transcription of NF-κB p65 by binding to the p65 promoter. ► Nuclear IL-33 controls NF-κB-dependent inflammatory responses. Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine...

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Published in:Biochemical and biophysical research communications 2012-05, Vol.421 (2), p.305-311
Main Authors: Choi, Yeon-Sook, Park, Jeong Ae, Kim, Jihye, Rho, Seung-Sik, Park, Hyojin, Kim, Young-Myeong, Kwon, Young-Guen
Format: Article
Language:English
Subjects:
Cell Adhesion - genetics
Cell adhesion molecules
Cell Nucleus - metabolism
Cells, Cultured
Endothelial Cells - metabolism
Gene Knockdown Techniques
High endothelial venules
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Inflammation
Inflammation - genetics
Intercellular Adhesion Molecule-1 - genetics
Interleukin-33
Interleukins - metabolism
Monocytes - physiology
NF-HEV
NF-κB p65
Promoter Regions, Genetic
Transcription Factor RelA - genetics
Transcriptional Activation
Tumor Necrosis Factor-alpha - pharmacology
Vascular Cell Adhesion Molecule-1 - genetics
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Summary:► IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. ► Nuclear IL-33 increased the transcription of NF-κB p65 by binding to the p65 promoter. ► Nuclear IL-33 controls NF-κB-dependent inflammatory responses. Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-κB complex and is involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-α-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-κB pathway; NF-κB p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-κB p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-κB p65.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2012.04.005