Interleukin-33 (IL-33) was initially discovered as a nuclear factor NF-HEV abundantly expressed in high endothelial venules. It is a 30-32 kD pro-inflammatory protein with intracellular and extracellular activities and a chromatin-associated cytokine of the IL-1 family with high sequence and structural similarity to IL-1 and IL-18. IL-33 is highly and selectively expressed by high endothelial venule endothelial cells (HEVECs) in human tonsils, Peyers's patches, and lymph nodes. It contains a bipartite nuclear localization signal at the C-terminus, and is targeted to the nucleus when ectopically expressed in human umbilical vein endothelial cells (HUVECs) and HeLa cells. The C-terminal fragment, corresponding to mature IL-33, binds and triggers signaling. IL-33 mediates its biological effects via Toll-interleukin 1 (IL-1) receptor (TIR) domain-containing receptor ST2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs. Human IL-33 is 270 amino acids in length.