IL-1 (Interleukin 1) Family Ligand Review

Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. IL-1 family ligands include seven molecules 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). The IL-1 family ligand members include 11 molecules.

These members are classified into IL-1 (Interleukin 1) Family Ligands, mainly based on similar amino acid sequence, gene structure, and three-dimensional structure.

The following will briefly highlight each IL-1 family ligand and also present its key functions. As depicted in the below picture, IL-1 family ligands can be divided into subfamilies according to the length of the precursor and the length of the propiece for each precursor. The N-terminal cleavage site (N) is located 9 amino acids before the AXD site, a conserved motif, where A is an aliphatic amino acid, X is any amino acid and D is aspartic acid. A-X-D motif plays a role in the folding and tertiary structure of active IL-1 family members. IL-37 has been identified only in humans. The N-terminus of IL-1Ra is generated by a signal peptide.

IL-1 family ligands subfamily

1. IL-1 subfamily: IL-1α (IL-1F1), IL-1β (IL-1F2) and IL-33 (IL-1F11)

Each member of IL-1 family binds to a ligand binding chain, often termed the α chain. IL-1α and IL-1β are encoded by distinct genes, bind to the same receptor (IL-1R1), and have similar biological properties.

The original members of the IL-1 family ligands are IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1RA). IL-1α precursor is fully active and functions as an "alarmin" by rapidly initiating a cascade of inflammatory cytokines and chemokines, which accounts for sterile inflammation. circulating IL-1α is rarely detected even in persons with severe infections but is contained in apoptotic bodies released from endothelial cells.

IL-1β is produced by hematopoietic cells such as blood monocytes, tissue macrophages, skin dendritic cells, and brain microglia in response TLR, activated complement components, other cytokines (such as TNF-α), and IL-1 itself. Unlike the IL-1α precursor, the IL-1β precursor is not active but is cleaved by caspase-1, releasing the active cytokine into the extracellular space.

IL-33 (IL-1F11) belongs to the IL-1 family ligand. IL-33Rα is the ligand binding chain for IL-33, and the co-receptor for IL-33 is the IL-1RAcP, which is also the co-receptor for IL-1α and IL-1β. The IL-33Rα chain is similar to IL-1R1, since it can bind the ligand but requires the IL-1RAcP to signal.

IL-33 is released as a bioactive molecule mainly upon necrotic cell death or secreted by unconventional mechanisms. As for other IL-1 family ligand members, calpain and the neutrophil serine proteases cathepsin G and elastase cleave human IL-33 and generate more potent mature forms.

2. IL-1 receptor antagonist: IL-1Ra (IL-1F3)

The IL-1 ligand family includes two receptor antagonists, IL-1Ra and IL-36Ra. IL-1Ra binds IL-1R1 with an affinity higher than that of IL-1 but fails to recruit the IL-1RAcP. In addition to secreted soluble IL-1Ra, there are the two intracellular isoforms which are considered a reservoir of IL-1Ra, to be released upon cell death, limiting the proinflammatory action of tissue damage.

3. IL-18 subfamily: IL-18 (IL-1F4) and IL-37 (IL-1F7)

In addition to IL-1α and IL-1β, the IL-1 family ligand includes IL-18. IL-18 has its own ligand binding chain (IL-1R5). IL-18 is an important component of polarized Th1 cell and natural killer (NK) cell responses and of the interplay between macrophages and NK cells.

IL-37 (IL-1F7), an IL-1 family ligand member, has five splice variants, and isoform IL-37b is the most complete. Although IL-1β or TLRs increase IL-37, the anti-inflammatory cytokine-transforming growth factor-β (TGF-β) was the most effective stimulus.

Similar to IL-1α and IL-33, IL-37 is found in the nucleus where the cytokine functions in transcription suppressing gene expression. The nuclear translocation and anti-inflammatory properties of IL-37 appear to be linked to binding to the Smad3 transcription factor for the anti-inflammatory and immunosuppressive properties of TGF-β.

4. IL-36 subfamily: IL-36α (IL-1F6), IL-36β (IL-1F8), IL-36γ (IL-1F9), IL-36Ra (IL-1F5) and IL-38(IL-1F10)

IL-36 family members IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) bind to IL-1Rrp2 and use IL-1RAcP as a coreceptor. IL-36Ra (IL-1F5), which shares more than 50% homology with IL-1Ra, but is unable to bind to the IL-1R1 since it significantly differs in loop conformations from IL-1Ra. IL-36Ra is a receptor antagonist for IL-1Rrp2 and prevents the activity of IL-36.

IL-36α, IL-36β, IL-36γ, and IL-36Ra do not contain caspase cleavage sites and N-terminal truncation at the level of the A-X-Asp motif conserved in all IL-1 family ligand members dramatically increases their proinflammatory activity.

IL-38 gene is located in the IL-1 family cluster on chromosome 2 next to the genes encoding IL-1Ra and IL-36Ra. IL-38 shares 41% homology with IL-1Ra, a 43% homology with IL-36Ra and has a three-dimensional structure similar to IL-1Ra.

References

1. Veerdonk, F. V. D., & Netea, M. (2013). New insights in the immunobiology of IL-1 family members. Frontiers in immunology, 4, 167.
2. Garlanda, C., Dinarello, C. A., & Mantovani, A. (2013). The interleukin-1 family: back to the future. Immunity, 39(6), 1003-1018.
3. Dinarello, C. A. (2013). Overview of the interleukin-1 family of ligands and receptors. Semin Immunol, 25(6), 389-393.