The family of the interleukin‐1 receptors

Summary The extracellular forms of the IL‐1 cytokines are active through binding to specific receptors on the surface of target cells. IL‐1 ligands bind to the extracellular portion of their ligand‐binding receptor chain. For signaling to take place, a non‐binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll‐IL‐1‐receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL‐1 receptors (IL‐1R) includes 10 structurally related members, and the distantly related soluble protein IL‐18BP that acts as inhibitor of the cytokine IL‐18. Over the years the receptors of the IL‐1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand‐binding chains (IL‐1R1, IL‐1R2, IL‐1R4, IL‐1R5, and IL‐1R6), 2 types of accessory chains (IL‐1R3, IL‐1R7), molecules that act as inhibitors of signaling (IL‐1R2, IL‐1R8, IL‐18BP), and 2 orphan receptors (IL‐1R9, IL‐1R10). In this review, we will examine how the receptors of the IL‐1 family regulate the inflammatory and anti‐inflammatory functions of the IL‐1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL‐1/IL‐1R system in the brain will be also described, as an example of the peculiarities of organ‐specific modulation of inflammation.