IL36RN gene

The IL36RN gene (IL36RN stands for: interleukin-36 receptor antagonist) is a protein-coding gene located on chromosome 2q14.1. Two alternatively spliced transcript variants encoding the same protein are known. The IL36RN gene and eight other interleukin-1 family genes form a cytokine gene cluster on chromosome 2.

The protein encoded by the IL36RN gene, the IL-36 receptor antagonist IL-36Ra, is a member of the interleukin-1 cytokine family. This protein is found primarily in the skin, where it helps regulate inflammation that is part of the body's early immune response. These immunological responses are initiated when other cytokines such as IL-36 alpha (α), IL-36 beta (β), or IL-36 gamma (γ) bind to the common receptor.

This binding activates pro-inflammatory signaling pathways, namely the NF-κB and MAPK pathways. The IL-36a protein controls these activities by competitively binding to the IL-36Ra- receptor protein. This prevents IL-36alpha, IL-36beta, and IL-36gamma from docking to this receptor. IL-36RA thus inhibits the activity of interleukin-36 (IL36A, IL36B and IL36G).

Evidence suggests that this cytokine specifically inhibits the activation of NF-kappaB induced by interleukin 1 family, member 6 (IL1F6).

Furthermore, the encoded protein may be involved in the innate immune response to fungal pathogens such as Aspergillus fumigatus by activating an anti-inflammatory signaling pathway through recruitment of SIGIRR.

IL36RN gene mutations are also associated with various inflammatory skin diseases that are accompanied by pustule formation. For example, generalized pustular psoriasis (GPP/Zumbusch type) (Farooq M et al. 2013).

Other IL36RN-associated diseases are classified as forms of localized pustular psoriasis, as the blisters only occur in limited areas of the body:

• Palmoplantar pustulosis (PPPP), for example, affects the hands and feet, and Hallopeau's acrodermatitis continua affects the tips of the fingers and toes. It is unclear how mutations in one and the same gene can cause these clinically distinct diseases.
• IL36RN gene mutations have also been found in people with lingua geographica (Liang J et al. 2017).
• In individual cases, mutations in this gene have also been detected in acute generalized exanthematous pustulosis(AGEP) (usually triggered by medication) (Chadli Z et al. 2018). This indicates a pathogenetic relationship between GPP and AGEP.

With the IL36 receptor inhibitor spesolimab (Spevigo®), an efficient drug for the indication "psoriasis pustulosa generalisata" has been available since January 2023 (Choon SE et al. 2021).

1. Chadli Z et al (2018) Codeine-induced acute generalized exanthematous pustulosis without IL36RN mutations. Pharmacogenomics 19:889-893.
2. Choon SE et al (2021) Study protocol of the global Effisayil 1 phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare. BMJ Open 11:e043666.
3. Farooq M et al (2013) Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 34:176-83.
4. Hussain S et al (20159 IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis. J Allergy Clin Immunol 135:1067-1070.
5. Kardaun SH et al (2010) The histopathological spectrum of acute generalized exanthematous pustulosis (AGEP) and its differentiation from generalized pustular psoriasis. J Cutan Pathol 37(12):1220-1229.
6. Korber A et al (2013) Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol 133:2634-2637.
7. Liang J et al (2017) Mutations in IL36RN are associated with geographic tongue. Hum Genet 136:241-252.
8. Onoufriadis A et al (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 89:432-437.
9. Setta-Kaffetzi N et al (2013) Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 133:1366-1369.
10. Tauber M et al (2016) IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases. J Invest Dermatol 136:1811-1819.