IL‐1, IL‐18, and IL‐33 families of cytokines

Summary: The interleukin‐1 (IL‐1), IL‐18, and IL‐33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase‐1 before or during release from the cell. The NALP‐3 inflammasome is of crucial importance in generating active caspase‐1. The IL‐1 family contains two agonists, IL‐1α and IL‐1β, a specific inhibitor, IL‐1 receptor antagonist (IL‐1Ra), and two receptors, the biologically active type IL‐1R and inactive type II IL‐1R. Both IL‐1RI and IL‐33R utilize the same interacting accessory protein (IL‐1RAcP). The balance between IL‐1 and IL‐1Ra is important in preventing disease in various organs, and excess production of IL‐1 has been implicated in many human diseases. The IL‐18 family also contains a specific inhibitor, the IL‐18‐binding protein (IL‐18BP), which binds IL‐18 in the fluid phase. The IL‐18 receptor is similar to the IL‐1 receptor complex, including a single ligand‐binding chain and a different interacting accessory protein. IL‐18 provides an important link between the innate and adaptive immune responses. Newly described IL‐33 binds to the orphan IL‐1 family receptor T1/ST2 and stimulates T‐helper 2 responses as well as mast cells.