title: Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells.
abstract: OBJECTIVE
  Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1β, as a reference.
  
  
  RESULTS
  Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1β, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1β and led us to observe that quiescent endothelial cells (ppRb(low)p27(high)) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness.
  
  
  CONCLUSIONS
  In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.
authors.affiliation: LIIPAT, Institute of Pathology, University of Oslo, Oslo, Norway.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pollheimer
authors.forename: Johanna
authors.initials: J
authors.lastname: Bodin
authors.forename: Olav
authors.initials: O
authors.lastname: Sundnes
authors.forename: Reidunn J
authors.initials: RJ
authors.lastname: Edelmann
authors.forename: Sigrid S
authors.initials: SS
authors.lastname: Skånland
authors.forename: Jon
authors.initials: J
authors.lastname: Sponheim
authors.forename: Mari Johanna
authors.initials: MJ
authors.lastname: Brox
authors.forename: Eirik
authors.initials: E
authors.lastname: Sundlisaeter
authors.forename: Tamara
authors.initials: T
authors.lastname: Loos
authors.forename: Morten
authors.initials: M
authors.lastname: Vatn
authors.forename: Monika
authors.initials: M
authors.lastname: Kasprzycka
authors.forename: Junbai
authors.initials: J
authors.lastname: Wang
authors.forename: Axel M
authors.initials: AM
authors.lastname: Küchler
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.forename: Guttorm
authors.initials: G
authors.lastname: Haraldsen
authors.forename: Johanna
authors.initials: J
authors.lastname: Hol
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D034622:RNA Interference; D018123:Receptors, Interleukin / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; D019040:E-Selectin; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D018123:Receptors, Interleukin; D016160:Retinoblastoma Protein; C546936:SELE protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases