Nuclear Interleukin-33 Is Generally Expressed in Resting Endothelium but Rapidly Lost upon Angiogenic or Proinflammatory Activation

Axel M. Küchler^*, Jürgen Pollheimer^*, Johanna Balogh^*, Jon Sponheim^*¶, Linda Manley^*, Dag R. Sorensen, Paula M. De Angelis, Helge Scott^* and Guttorm Haraldsen^*

From the Laboratory for Immunology and Immunopathology (LIIPAT) at the Division of Pathology,^* the Division of Pathology, Rikshospitalet University Hospital; the Institute of Pathology, and the Center for Comparative Medicine, University of Oslo, Oslo; and the Department of Internal Medicine,^¶ Asker and Baerum Hospital, Rud, Norway

Interleukin (IL)-33 is a novel member of the IL-1 family ofcytokines that promotes Th2 responses in lymphocytes as wellas the activation of both mast cells and eosinophils via theST2 receptor. Additionally, IL-33 has been proposed to act asa chromatin-associated transcriptional regulator in both endothelialcells of high endothelial venules and chronically inflamed vessels.Here we show that nuclear IL-33 is expressed in blood vesselsof healthy tissues but down-regulated at the earliest onsetof angiogenesis during wound healing; in addition, it is almostundetectable in human tumor vessels. Accordingly, IL-33 is inducedwhen cultured endothelial cells reach confluence and stop proliferatingbut is lost when these cells begin to migrate. However, IL-33expression was not induced by inhibiting cell cycle progressionin subconfluent cultures and was not prevented by antibody-mediatedinhibition of VE-cadherin. Conversely, IL-33 knockdown did notinduce detectable changes in either expression levels or thecellular distribution of either VE-cadherin or CD31. However,activation of endothelial cell cultures with either tumor necrosisfactor- ${alpha}$ or vascular endothelial growth factor and subcutaneousinjection of these cytokines led to a down-regulation of vascularIL-33, a response consistent with both its rapid down-regulationin wound healing and loss in tumor endothelium. In conclusion,we speculate that the proposed transcriptional repressor functionof IL-33 may be involved in the control of endothelial cellactivation.