The interleukin-1 receptor family.

The cytokines IL-1 and IL-18 are key molecules both in the innate and in the adaptive immune response. Their activity is mediated by specific receptors present on the membrane of target cells. It has become apparent that these receptors are members of a larger family of related receptors, most of which are apparently involved in the mechanisms of host defense. Thus, the large Toll/IL-1R (TIR) superfamily encompasses the Ig domain family (IL-1 receptors, IL-18 receptors, and IL-1R-like receptors), the leucine-rich domain family [the Toll-like receptors (TLR) and similar receptors], and a series of TIR domain-containing intracellular adapter molecules. The TIR superfamily is defined by a common intracellular TIR domain, involved in the initiation of signaling. A group of TIR domain-containing adapters (MyD88, TIRAP, TRIF, and TRAM) are differentially recruited to the Toll/IL-1 receptors, contributing to the specificity of signaling. Recent studies have also begun to unravel the mechanisms of negative regulation of the Toll/IL-1 receptors. The orphan receptor TIR8/SIGIRR, a member of TIR superfamily, while unable to initiate signaling, can negatively modulate the TIR-mediated responses. Other negative regulators of the Toll/IL-1R family include T1/ST2, some soluble forms of TLR, and MyD88s. The coordinated positive and negative regulation of the TIR activation ensures the appropriate modulation of the innate and inflammatory responses and avoids the risk of pathological derangement. This chapter will consider in detail the characteristics and functional role of the Ig domain receptor subfamily in the regulation of host defense and their possible role in pathology.