Overview of the IL-1 family in innate inflammation and acquired immunity

Abstract

The interleukin-1 (IL-1) family of cytokines and receptors is unique in immunology because the IL-1 family and Toll-like receptor (TLR) families share similar functions. More than any other cytokine family, the IL-1 family is primarily associated with innate immunity. More than 95% of living organisms use innate immune mechanisms for survival whereas less than 5% depend on T- and B-cell functions. Innate immunity is manifested by inflammation, which can function as a mechanism of host defense but when uncontrolled is detrimental to survival. Each member of the IL-1 receptor and TLR family contains the cytoplasmic Toll-IL-1-Receptor (TIR) domain. The 50 amino acid TIR domains are highly homologous with the Toll protein in Drosophila. The TIR domain is nearly the same and present in each TLR and each IL-1 receptor family. Whereas IL-1 family cytokine members trigger innate inflammation via IL-1 family of receptors, TLRs trigger inflammation via bacteria, microbial products, viruses, nucleic acids, and damage-associated molecular patterns (DAMPs). In fact, IL-1 family member IL-1a and IL-33 also function as DAMPs. Although the inflammatory properties of the IL-1 family dominate in innate immunity, IL-1 family member can play a role in acquired immunity. This overview is a condensed update of the IL-1 family of cytokines and receptors.

Keywords: acquired immunity; cytokines; host defense; immunity; inflammation; innate immunity.

FIGURE 1

The 3 subfamilies of the IL-1 family. The number of amino acids is indicated at the end of each cytokine precursor. The IL-1 family consensus sequence AXD is indicated for each cytokine, and the 9 amino acids preceding the AXD site is indicated by a vertical bar. The vertical bar indicates the location of the optimal N-terminus. A red circle represents the members with primary pro-inflammatory properties, whereas a green circle represents cytokines that are anti-inflammatory. Because IL-1Ra has a signal peptide and is readily secreted, there is no AXD site. Adapted from

FIGURE 2

Resting and activation state of IL-1 receptors. In the resting state (left), the ligand binding chain, IL-1R1, is present on all nucleated cells. IL-1R3 is also present in the same cell. Both receptors are integral membrane proteins. Upon the binding of either IL-1α or IL-1β to the third Ig domain of IL-1R1, the receptor undergoes a structural change (left). This structural change allows the coreceptor, IL-1R3, to bind and form a trimeric complex. The intracellular TIR domains of IL-1R1 and IL-1R3 approximate and MyD88 now binds to the TIR domains. MyD88 becomes phosphorylated and other kinases (IL-1 receptor activated kinases (IRAKs) 1–4, data not shown) participate in a strong pro-inflammatory signal to the nucleus