title: IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo.
abstract: Recent studies indicate that IL-1alpha functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo. Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix-turn-helix motif. Together, these data suggest that, similarly to IL1alpha and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.
authors.affiliation: Laboratoire de Biologie Vasculaire, Equipe Labellisée "La Ligue 2006," Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, 205 Route de Narbonne, 31077 Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Carriere
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ortega
authors.forename: Delphine-Armelle
authors.initials: DA
authors.lastname: Lacorre
authors.forename: Laure
authors.initials: L
authors.lastname: Americh
authors.forename: Luc
authors.initials: L
authors.lastname: Aguilar
authors.forename: Gérard
authors.initials: G
authors.lastname: Bouche
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
mesh_terms: D016475:3T3 Cells; D020816:Amino Acid Motifs; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D017124:Conserved Sequence; D003424:Crohn Disease / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006367:HeLa Cells; D006570:Heterochromatin / Q000737:chemistry*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008938:Mitosis; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000502:physiology*; D018123:Receptors, Interleukin; D012097:Repressor Proteins / Q000502:physiology
chemical_list: D006570:Heterochromatin; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D012097:Repressor Proteins