The interleukin-1 (IL-1) family of receptors and cytokines are potent molecules of the innate immune system, involved in mechanisms of host defence. Upon binding of a cytokine to its receptor, a co-receptor is recruited to form a ternary signalling complex. The signal transduction pathways typically result in a pro-inflammatory response; hence inflammatory pathways involving members of the IL-1 family pose as likely targets for therapeutic intervention and have materialized in the treatment of acute and chronic inflammatory diseases. To date, the following IL-1 receptor (IL-1R) family members have been described and include four ligand-binding chains IL-1R1, IL-18Rα, IL-1Rrp2 and ST2, three orphan receptors, two proteins that act as co-receptors and a decoy receptor, which is unable to initiate signal transduction.These molecules share a similar structure of typically three extracellular immunoglobulin-like domains, a transmembrane region and a conserved intracellular Toll/IL-1R domain. Several of these receptors have been implicated in inflammatory disease; in particular, IL-18Rα has been linked to disorders such as multiple sclerosis and rheumatoid arthritis.

We aim to structurally and functionally characterise the interaction of human IL-18Rα with its physiological binding partners. To date, the third extracellular domain of IL-18Rα has been expressed, purified in an Escherichia coli expression system and its structure solved by X-ray crystallography to 2.1 Å. Furthermore, the whole extracellular domain has been purified from a baculovirus expression system and the sites of N-glycosylation determined by mass spectrometry. Surface plasmon resonance analysis has determined that IL-18Rα interacts with its physiological binding partner IL-18 with a K_D of ~ 66 nM. These structural and functional data will lead to a comprehensive understanding of receptor-ligand activation of IL-18Rα, and in turn, create a platform for the screening and development of anti-inflammatory therapeutics.