Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation.
Interleukin (IL)-33 is a novel member of the IL-1 family of cytokines that promotes Th2 responses in lymphocytes as well as the activation of both mast cells and eosinophils via the ST2 receptor. Additionally, IL-33 has been proposed to act as a chromatin-associated transcriptional regulator in both endothelial cells of high endothelial venules and chronically inflamed vessels. Here we show that nuclear IL-33 is expressed in blood vessels of healthy tissues but down-regulated at the earliest onset of angiogenesis during wound healing; in addition, it is almost undetectable in human tumor vessels. Accordingly, IL-33 is induced when cultured endothelial cells reach confluence and stop proliferating but is lost when these cells begin to migrate. However, IL-33 expression was not induced by inhibiting cell cycle progression in subconfluent cultures and was not prevented by antibody-mediated inhibition of VE-cadherin. Conversely, IL-33 knockdown did not induce detectable changes in either expression levels or the cellular distribution of either VE-cadherin or CD31. However, activation of endothelial cell cultures with either tumor necrosis factor-alpha or vascular endothelial growth factor and subcutaneous injection of these cytokines led to a down-regulation of vascular IL-33, a response consistent with both its rapid down-regulation in wound healing and loss in tumor endothelium. In conclusion, we speculate that the proposed transcriptional repressor function of IL-33 may be involved in the control of endothelial cell activation.
Küchler
Axel M
AM
Laboratory for Immunology and Immunopathology, Division of Pathology, Rikshospitalet University Hospital, Oslo, Norway.
Pollheimer
Jürgen
J
Balogh
Johanna
J
Sponheim
Jon
J
Manley
Linda
L
Sorensen
Dag R
DR
De Angelis
Paula M
PM
Scott
Helge
H
Haraldsen
Guttorm
G
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006262:Health; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D016207:Cytokines; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A
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