Interleukin-33 biology with potential insights into human diseases

Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is a nuclear protein that is also released into the extracellular space, and thus acts as a dual-function molecule, as does IL-1 alpha. Extracellular IL-33 binds to the cell-surface receptor ST2, leading to the activation of intracellular signaling pathways similar to those used by IL-1. Unlike conventional cytokines, IL-33 might be secreted via unconventional pathways, and can be released upon cell injury as an alarmin. IL-33 is expressed in cells that are in contact with the environment, and acts as an early inducer of inflammation. Its production is then upregulated in inflamed tissues, thus contributing to the further amplification of inflammatory responses. Studies of IL-33-deficient mice will provide more information on intracellular functions of this cytokine. A large body of evidence supports the pathogenic role of IL-33 in asthma and possibly other inflammatory airway conditions. Furthermore, IL-33 has been shown to be involved in experimental models of arthritis and potentially has a pathogenic role in ulcerative colitis and fibrotic conditions, suggesting that IL-33 antagonists might be of interest for the treatment of asthma, rheumatoid arthritis and ulcerative colitis. However, IL-33 also appears to exert important functions in host defense against pathogens and to display cardioprotective properties, which might have implications for the clinical use of IL-33 blockade.