The interleukin-1 family: back to the future

Abstract

Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.

Fig. 1

Panel A. A schematic representation of ligands and receptor chains in the IL-1 family. The minus sign indicates inhibition. TIR8 (also known as SIGIRR) has two aminoacid substitutions (Cys222 and Leu305 for canonical Ser447 and Tyr536). Panel B. Subfamilies among IL-1 ligands, divided based on the length of the N-terminal prodomain. Numbers refer to aminoacids. The cleavage site (N) is located 9 amino acids N-terminal to AXD, a conserved motif, where A is an aliphatic amino acid. IL-37 has been identified only in man.

Fig. 2

A schematic representation of role of IL-1 (panel A) and IL-33 (panel B) in innate and adaptive immunity. “+IL-12” refers to costimulation by IL-33 + IL-12 of target cells. PRR, pattern recognition receptor; Nc Th1, non-conventional Th1; α1AT, α1 antitrypsin inhibitor; CRP, C reactive protein; PTX3, pentraxin 3; HPA, hypothalamus-pituitary-adrenal axis; FFA, free fatty acid.

Fig. 3

A schematic representation of role of IL-18 (Panel A) and IL-36 (Panel B) in innate and adaptive immunity. “+” refers to costimulation by IL-12, IL-23 or IL-15 of the action of IL-18 on target cells. SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; GvHD, graft versus host disease.

Fig. 4

Negative regulators of IL-1, IL-33, IL-18 and IL-36. icIL-1Ra, two isoforms of intracellular IL-1Ra.

Fig. 5

IL-1 family members in the differentiation and function of innate and adaptive lymphoid cells. “+” above arrows refers to stimulation of target cells by IL-1 family members with or without other cytokines (IL-12, IL-25, thymic stromal lymphopoietin (TSLP), IL-23). Arrows point to products of stimulated cells and cellular effectors (on the right part). ncTh1, non-conventional Th1 cells (human). The → → sign for the Th17 cells and Tγδ17 cells indicates the presence of intermediate cells (endothelium, epithelium) which respond to IL-17.