IL-33, also known as NF-HEV and DVS 27, is a 17.5 kDa proinflammatory protein that may also regulate gene transcription. DVS 27 was identifed as a gene that is upregulated in vasospastic cerebral arteries. NF-HEV was described as a nuclear factor that is preferentially expressed in the endothelial cells of high endothelial venules relative to endothelial cells from other tissues. IL-33 was identified based on sequence and structural homology with IL-1 family cytokines. DVS 27, NF-HEV, and IL-33 share 100% amino acid sequence identity. IL-33 is constitutively expressed in smooth muscle and airway epithelia. It is upregulated in arterial smooth muscle, dermal fibroblasts, and keratinocytes following IL-1 alpha or IL1 beta stimulation. Similar to IL-1, IL-33 can be cleaved in vitro by caspase1, generating an Nterminal fragment that is slightly shorter than the Cterminal fragment. The Nterminal portion of full length IL-33 contains a predicted bipartite nuclear localization sequence and a homeodomain-like helix-turn-helix DNA binding domain. By immunofluorescence, full length IL-33 localizes to the nucleus in HUVECs and transfectants. The Cterminal fragment, corresponding to mature IL-33, binds and triggers signaling through mast cell IL1 R4/ST2L, a longtime orphan receptor involved in the augmentation of Th2 cell responses. A ternary signaling complex is formed by the subsequent association of IL-33 and ST2L with IL1 RAcP. Stimulation of Th2 polarized lymphocytes with mature IL-33 in vitro induces IL-5 and IL-13 secretion. In vivo administration of mature IL-33 promotes increased production of IL-5, IL-13, IgE, and IgA, as well as splenomegaly and inflammatory infiltration of mucosal tissues. Full length and mature mouse IL-33 share approximately 55% and 90% aa sequence identity with human and rat IL-33, respectively. Mouse IL-33 shares less than 25% aa sequence identity with other IL-1 family proteins.