IL-33 is a member of the IL-1 superfamily of cytokines, a determination based in part on the molecules β-trefoil structure, a conserved structure type described in other IL-1 cytokines, including IL-1α, IL-1β, IL-1Ra and IL-18. In this structure, the 12 β-strands of the β-trefoil are arranged in three pseudorepeats of four β-strand units, of which the first and last β-strands are antiparallel staves in a six-stranded β-barrel, while the second and third β-strands of each repeat form a β-hairpin sitting atop the β-barrel. IL-33 is a ligand that binds to a high-affinity receptor family member ST2. The complex of these two molecules with IL-1RAcP indicates a ternary complex formation. The binding area appears to be a mix of polar and non-polar regions that create a specific binding between ligand and receptor. The interface between the molecules has been shown to be extensive. Structural data on the IL-33 molecule was determined by solution NMR and small angle X-ray scattering.
IL-33 is constitutively located in the nucleus of structural cells of humans and mice and has a helix-turn-helix domain presumably allowing it to bind to DNA. There is a paucity of research into the nuclear role of IL-33 but amino acids 40-58 in human IL-33 are sufficient for nuclear localisation and histone binding. IL-33 also interacts with the histone methyltransferase SUV39H1 and murine appears to IL-33 interact to NF-κB.
As a cytokine, IL-33 interacts with the receptors ST2 (also known as IL1RL1) and IL-1 Receptor Accessory Protein (IL1RAP), activating intracellular molecules in the NF-κB and MAP kinase signaling pathways that drive production of type 2 cytokines (e.g. IL-5 and IL-13) from polarized Th2 cells. The induction of type 2 cytokines by IL-33 in vivo is believed to induce the severe pathological changes observed in mucosal organs following administration of IL-33. IL-33 is also effective in reversing Alzheimer-like symptoms in APP/PS1 mice, by reversing the buildup and preventing the new formation of amyloid plaques.
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