IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo

Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):282-7. doi: 10.1073/pnas.0606854104. Epub 2006 Dec 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Motifs
  • Animals
  • Arthritis, Rheumatoid / metabolism
  • Conserved Sequence
  • Crohn Disease / metabolism
  • Endothelial Cells / metabolism
  • HeLa Cells
  • Heterochromatin / chemistry*
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / chemistry
  • Interleukins / genetics
  • Interleukins / physiology*
  • Membrane Proteins / physiology*
  • Mice
  • Mitosis
  • Nuclear Localization Signals
  • Nuclear Proteins / physiology*
  • RNA, Messenger / analysis
  • Receptors, Cell Surface / physiology*
  • Receptors, Interleukin
  • Repressor Proteins / physiology


  • Heterochromatin
  • IL1RL1 protein, human
  • IL33 protein, human
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Membrane Proteins
  • Nuclear Localization Signals
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • Repressor Proteins