Interleukin-1 Receptor Antagonist

IL-1RA is the first naturally occurring receptor antagonist of a cytokine to be described. IL-1RA is a member of the interleukin-1 cytokine family according to three criteria:

• Amino acid sequence homology of 26 to 30 % to IL-1 beta and 19 % to IL-1 alpha
• similarities in the gene structure
• common gene localization on the human chromosome 2q14.

The interleukin (IL)-1 cytokine family comprises 11 members, including:

• 7 proinflammatory agonists(IL-1alpha, IL-1beta, IL-18, IL-33, IL-36alpha, IL-36beta, IL-36gamma)
• and
• 4 defined antagonists(IL-1Ra, IL-36Ra, IL-37 and IL-38), which exert anti-inflammatory activities.

The family of IL-1 receptors (IL-1R) comprises 10 members with cytokine-specific receptors, co-receptors and inhibitory receptors.

IL-1RA is encoded by the IL-1 receptor antagonist gene(IL1RN gene) on chromosome 2q14.1.

There are two structural variants of IL-1RA:

• sIL-1RA, a secretory molecule produced by monocytes, macrophages, neutrophils, fibroblasts and other cells

and

• icIL-1RA, an intracellular molecule produced by keratinocytes (Corradi A et al. 1995) and other epithelial cells as well as by macrophages, fibroblasts, monocytes, neutrophils, keratinocytes and bronchial epithelial cells (Higgins GC et al. 1999).

IL-1RA production by monocytes, macrophages and neutrophils can be regulated in different ways by interleukin-1beta. IL-1RA binds to both IL-1RIs and IL-1RIIs on cell surfaces, but with a 100-fold higher avidity compared to IL-1RIs.

IL-1RA competitively inhibits the binding of interleukin-1alpha and interleukin-1beta to cell surface receptors without triggering recognizable intracellular responses. All three forms of inereleukin-1 can bind to IL-1 receptors in a similar manner. However, IL-1RA may lack the secondary interactions required to trigger cellular responses. The receptor antagonist thus contributes to the control of the inflammatory process.

The role of sIL-1RA and icIL-1RA in normal physiology or host defense mechanisms remains unclear (Martin P et al. 2020). The preliminary results of clinical trials in humans indicate a potential efficacy of IL-1RA in sepsis, rheumatoid arthritis and GVHD. IL-1RA is used for the treatment of rheumatoid arthritis. It is produced commercially as a recombinant form of IL-1ra and is called Anakinra.

Mutations in the gene encoding IL-1RA are associated with interleukin-1 receptor antagonist deficiency syndrome (DIRA). DIRA is a life-threatening, rare, autosomal recessive, autoinflammatory syndrome due to loss-of-function (LOF) mutations in the IL-1 receptor antagonist gene(IL1RN gene). Its loss of function leads to continuous pro-inflammatory signaling and to the systemic reactions of the disease.

1. Corradi A et al. (1995) Synthesis and secretion of interleukin-1 alpha and interleukin-1 receptor antagonist during differentiation of cultured keratinocytes. Exp Cell Res 217(2):355-362.
2. Higgins GC et al. (1999) Intracellular IL-1 receptor antagonist is elevated in human dermal fibroblasts that overexpress intracellular precursor IL-1 alpha. J Immunol 163+:3969-3975.
3. Martin P et al. (2020) Intracellular IL-1 Receptor Antagonist Isoform 1 Released from Keratinocytes upon Cell Death Acts as an Inhibitor for the Alarmin IL-1α. J Immunol 204:967-979.
4. Palomo J et al.(2015) The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25-37.