Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation.
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-a-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.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Yeon-Sook
YS
Choi
Jeong Ae
JA
Park
Jihye
J
Kim
Seung-Sik
SS
Rho
Hyojin
H
Park
Young-Myeong
YM
Kim
Young-Guen
YG
Kwon
D002448:Cell Adhesion / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D009000:Monocytes / Q000502:physiology; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000235:genetics*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1