title: Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation.
abstract: 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.
authors.affiliation: Laboratory for Immunology and Immunopathology, Division of Pathology, Rikshospitalet University Hospital, Oslo, Norway.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Küchler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pollheimer
authors.forename: Johanna
authors.initials: J
authors.lastname: Balogh
authors.forename: Jon
authors.initials: J
authors.lastname: Sponheim
authors.forename: Linda
authors.initials: L
authors.lastname: Manley
authors.forename: Dag R
authors.initials: DR
authors.lastname: Sorensen
authors.forename: Paula M
authors.initials: PM
authors.lastname: De Angelis
authors.forename: Helge
authors.initials: H
authors.lastname: Scott
authors.forename: Guttorm
authors.initials: G
authors.lastname: Haraldsen
mesh_terms: 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
chemical_list: D016207:Cytokines; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A
references.citation: J Exp Med. 2008 Feb 18;205(2):339-46
references.pmid: 18268038
references.citation: Cancer Res. 1994 Jul 1;54(13):3407-12
references.pmid: 8012959
references.citation: Lab Invest. 2007 Oct;87(10):971-8
references.pmid: 17700564
references.citation: N Engl J Med. 1986 Dec 25;315(26):1650-9
references.pmid: 3537791
references.citation: Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):663-8
references.pmid: 9012841
references.citation: J Clin Invest. 2007 Jun;117(6):1538-49
references.pmid: 17492053
references.citation: J Cell Biochem. 2000 Apr;77(3):465-73
references.pmid: 10760954
references.citation: Gut. 1995 Aug;37(2):225-34
references.pmid: 7557573
references.citation: Eur J Immunol. 2007 Oct;37(10):2779-86
references.pmid: 17853410
references.citation: Nature. 1990 Jul 19;346(6281):274-6
references.pmid: 2374592
references.citation: J Immunol. 2007 Aug 15;179(4):2551-5
references.pmid: 17675517
references.citation: Nat Rev Cancer. 2003 Jun;3(6):401-10
references.pmid: 12778130
references.citation: Cell Commun Signal. 2006 Aug 08;4:6
references.pmid: 16895594
references.citation: Am J Pathol. 2003 Jul;163(1):69-79
references.pmid: 12819012
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9815-20
references.pmid: 10449777
references.citation: Clin Exp Metastasis. 2002;19(3):247-58
references.pmid: 12067205
references.citation: Am J Physiol. 1997 Nov;273(5):H2396-405
references.pmid: 9374777
references.citation: Cytokine. 2007 Dec;40(3):216-25
references.pmid: 18023358
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2434-9
references.pmid: 14983027
references.citation: Microvasc Res. 2000 Mar;59(2):265-77
references.pmid: 10684732
references.citation: J Cereb Blood Flow Metab. 1999 Nov;19(11):1279-88
references.pmid: 10566975
references.citation: Science. 1983 Feb 25;219(4587):983-5
references.pmid: 6823562
references.citation: Am J Pathol. 1997 Jun;150(6):2113-23
references.pmid: 9176402
references.citation: J Leukoc Biol. 2008 Sep;84(3):631-43
references.pmid: 18552204
references.citation: Genes Cells. 2001 Feb;6(2):79-86
references.pmid: 11260253
references.citation: J Clin Invest. 1973 Nov;52(11):2745-56
references.pmid: 4355998
references.citation: Lab Invest. 2000 Jan;80(1):99-115
references.pmid: 10653008
references.citation: Cell. 1995 May 5;81(3):323-30
references.pmid: 7736585
references.citation: Blood. 2001 Mar 15;97(6):1679-84
references.pmid: 11238107
references.citation: Lancet. 2001 Feb 17;357(9255):539-45
references.pmid: 11229684
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):282-7
references.pmid: 17185418
references.citation: Nature. 1990 Dec 6;348(6301):555-7
references.pmid: 1701033
references.citation: Nature. 2002 Dec 19-26;420(6917):860-7
references.pmid: 12490959
references.citation: Microvasc Res. 2000 Jan;59(1):24-37
references.pmid: 10625568
references.citation: Nature. 1996 Apr 4;380(6573):435-9
references.pmid: 8602241
references.citation: J Exp Med. 1989 Aug 1;170(2):399-414
references.pmid: 2666561
references.citation: J Allergy Clin Immunol. 2008 Jun;121(6):1484-90
references.pmid: 18539196
references.citation: J Leukoc Biol. 2007 Dec;82(6):1481-90
references.pmid: 17881510
references.citation: J Biol Chem. 2004 Feb 6;279(6):4017-26
references.pmid: 14612453
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18660-5
references.pmid: 18003919
references.citation: J Cell Physiol. 2000 Mar;182(3):311-22
references.pmid: 10653597
references.citation: Lab Invest. 1991 Sep;65(3):334-46
references.pmid: 1716330
references.citation: Oncogene. 1997 Feb 13;14(6):629-40
references.pmid: 9038370
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: Immunity. 2005 Nov;23(5):479-90
references.pmid: 16286016
references.citation: Physiol Rev. 2003 Jul;83(3):835-70
references.pmid: 12843410
references.citation: J Invest Dermatol. 1992 Dec;99(6):683-90
references.pmid: 1361507