IL-33

Alias: Interleukin-33, IL-1F11

IL-33 is an IL-1 family member. It is a pro-inflammatory TH2 polarizing cytokine that enhances TH2 cell responses. IL-33 is not typically expressed by hematopoietic cells, but rather by fibroblasts, epithelial cells, and endothelial cells. In the absence of pro-inflammatory stimuli, IL-33 localizes to the nucleus, where in its uncleaved form, interacts with H2A and H2B. Mystery surrounds how IL-33 is secreted from cells and whether it is the cleaved or full-length protein that is active in vivo. The activating protein of IL-33 is still up for debate, though it is believed to be calpain that cleaves it to its mature form. IL-33 binds to ST2, an IL-1R family member receptor that is expressed on TH2, but not TH1 cells. Upon ligand binding, ST2 heterodimerizes with IL-1RAP that results in the activation of the NFκB and MAPK pathways. The activation of NFκB in mast cells results in mast cell degranulation and production of IL-1β, IL-3, IL-6, TNF, CXCL2, CCL2, CCL3, PGD2, and LTB4. IL-33 also acts directly on eosinophils to enhance their survival and adhesive properties, as well as their production of IL-8 and superoxide. In mast and T cells, the IL-33 activation of the MAPK pathways and induces the production of IL-5, IL-13, CCL5, CCL17, and CCL24. IL-33 is associated with infections, asthma, anaphylaxis, atherosclerosis, Alzheimer’s disease, pain, and arthritis, ulcerative colitis, and Crohn’s disease.