IL-1 antagonist discovery

Interleukin 1 (IL-1) is a pivotal pro-inflammatory cytokine involved in many types of inflammatory and autoimmune diseases [1]. IL-1 production whether initiated by infection or host antigen, initiates an inflammatory cascade which includes the induction of other mediators (e.g. IL-6, IL-8), upregulation of adhesion molecules (e.g. ICAM-1, E-selectin) and potent synergistic activity with other macrophage, proinflammatory cytokines (e.g. tumor necrosis factor) [2,3]. The IL-1 family consists of three structurally related naturally occurring ligands: two agonists, IL-1 α, and IL-1s; and one antagonist, the IL-1 receptor antagonist (IL-1RA) [4-6]. IL-1 is the only cytokine known to have a naturally occurring receptor antagonist. Two distinct cell membrane receptors have been characterized: The type I, IL-1 receptor (IL1RtI) responsible for biological responses; and the type II receptor (IL-1RtII), which is shed, and acts as a decoy to modulate IL-1 activity [7-11]. The existence of a naturally occurring antagonist and a decoy receptor further illustrates the importance and need for the tight regulation of IL-1 activity and its critical role in inflammation.