Interleukin 36

Interleukin 36, or IL-36, is a group of cytokines in the IL-1 family with pro-inflammatory effects. The role of IL-36 in inflammatory diseases is under investigation.[1]

There are four members of the IL-36 family which bind to the IL-36 receptor (IL1RL2/IL-1Rrp2/IL-36 receptor dimer) with varying affinities.[2] IL36A, IL36B, and IL36G are IL-36 receptor agonists. IL36RA is an IL-36 receptor antagonist, inhibiting IL-36R signaling. The agonists are known to activate NF-κB, mitogen-activated protein kinases, Erk1/2 and JNK through IL-36R/IL-1RAcP, which targets the IL-8 promotor and results in IL-6 secretion and induces various proinflammatory mediators.[3][4] Binding of the IL-36R agonists to IL-1Rrp2 recruits IL-1RAcP, activating the signaling pathway. IL-36Ra binds to IL-36R, preventing the recruitment of IL-1RAcP.[1]

Function

IL-36 has been found to activate T cell proliferation and release of IL-2.[5] Before the functions of the IL-36 cytokines were determined, they were named as derivatives of IL-1F; they were renamed to their current designations in 2010.[6]

Due to their predominant expression in epithelial tissues, IL-36 cytokines are believed to play a significant role in the pathogenesis of skin diseases, especially that of psoriasis.[6] IL-36 has also been linked to psoriatic arthritis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and Sjögren's syndrome.[1]

IL-36 must be cleaved at the N-terminus to become active, probable enzymes mediating the activation could be neutrophil granule-derived proteases, elastase, and cathepsin G, although they may activate the cytokines differentially.[7]

IL-36 is expressed by many cells types, most predominantly keratinocytes, respiratory epithelium, various nervous tissue, and monocytes.[6][1]

Genes and expression

The genes encoding for the IL-36 cytokines are found on chromosome 2q14.1.[8][9][10] All three are located in a cluster with other members of IL-1 family and the gene order from centromere to telomere is IL-1A-IL-1B-IL-37-IL-36G-IL-36A-IL-36B-IL-36RN-IL1F10-IL-1RN, and only IL-1A, IL-1B and IL-36B.[11] All of them probably arose from a common ancestral gene, which is most likely a primordial IL-1 receptor antagonist gene. [12]

All three genes are mainly expressed in keratinocytes, bronchial epithelium, brain tissue, and monocytes/macrophages. [6]

IL-36Ra is constitutively expressed in keratinocytes, whereas IL-36γ expression in keratinocytes is rapidly induced after stimulation with TNF or PMA (Phorbol 12-myristate 13-acetate). [13]

Clinical significance

IL-36-alpha functions primarily in skin and demonstrates increased expression in psoriasis. In addition, decreased expression of this gene has been linked to a poor prognosis in both hepatocellular carcinoma and colorectal cancer patients.[6]

IL-36 cytokines may play a regulatory role in the pathogenesis of inflammatory disorders such as folliculitis and eosinophilic pustular folliculitis. In addition, in acute generalized exanthematous pustulosis, IL-36 (mainly IL-36 gamma) was overexpressed in skin lesions.[14]

Studies revealed that T cells were sufficient to cause skin inflammation after Staphylococcus aureus exposure on mice, mediating the skin inflammation via IL-36-controlled, IL-17-dependent T cell responses.[15]

IL-36 is significantly involved in the pathogenesis of psoriasis leading to it being targeted therapeutically. Human psoriatic skin plaques displayed elevated IL-36beta. In addition, It was found that serum IL-36 levels are higher in patients with psoriasis vulgaris and it's levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful biomarkers in patients with psoriasis.[16]

References
  1. Ding L, Wang X, Hong X, Lu L, Liu D (January 2018). "IL-36 cytokines in autoimmunity and inflammatory disease". Oncotarget. 9 (2): 2895–2901. doi:10.18632/oncotarget.22814. PMC 5788690. PMID 29416822.
  2. Zhou L, Todorovic V, Kakavas S, Sielaff B, Medina L, Wang L, Sadhukhan R, Stockmann H, Richardson PL, DiGiammarino E, Sun C, Scott V (January 2018). "Quantitative ligand and receptor binding studies reveal the mechanism of interleukin-36 (IL-36) pathway activation". The Journal of Biological Chemistry. 293 (2): 403–411. doi:10.1074/jbc.M117.805739. PMC 5767850. PMID 29180446.
  3. Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE (December 2011). "Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β, and IL-36γ) or antagonist (IL-36Ra) activity". The Journal of Biological Chemistry. 286 (49): 42594–602. doi:10.1074/jbc.M111.267922. PMC 3234937. PMID 21965679.
  4. Towne, Jennifer E.; Garka, Kirsten E.; Renshaw, Blair R.; Virca, G. Duke; Sims, John E. (2004-04-02). "Interleukin (IL)-1F6, IL-1F8, and IL-1F9 Signal through IL-1Rrp2 and IL-1RAcP to Activate the Pathway Leading to NF-κB and MAPKs*". Journal of Biological Chemistry. 279 (14): 13677–13688. doi:10.1074/jbc.M400117200. ISSN 0021-9258. PMID 14734551.
  5. Vigne S, Palmer G, Martin P, Lamacchia C, Strebel D, Rodriguez E, Olleros ML, Vesin D, Garcia I, Ronchi F, Sallusto F, Sims JE, Gabay C (October 2012). "IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells". Blood. 120 (17): 3478–87. doi:10.1182/blood-2012-06-439026. PMID 22968459.
  6. Gresnigt MS, van de Veerdonk FL (December 2013). "Biology of IL-36 cytokines and their role in disease". Seminars in Immunology. 25 (6): 458–65. doi:10.1016/j.smim.2013.11.003. PMID 24355486.
  7. Sullivan, Graeme P.; Henry, Conor M.; Clancy, Danielle M.; Mametnabiev, Tazhir; Belotcerkovskaya, Ekaterina; Davidovich, Pavel; Sura-Trueba, Sylvia; Garabadzhiu, Alexander V.; Martin, Seamus J. (2018-03-07). "Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases". Cell Death & Disease. 9 (3): 378. doi:10.1038/s41419-018-0385-4. ISSN 2041-4889. PMC 5841435. PMID 29515113.
  8. "IL36A interleukin 36 alpha [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-09.
  9. "IL36B interleukin 36 beta [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-09.
  10. "IL36G interleukin 36 gamma [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-09.
  11. Dunn, Eleanor; Sims, John E; Nicklin, Martin J. H; O'Neill, Luke A. J (2001-10-01). "Annotating genes with potential roles in the immune system: six new members of the IL-1 family". Trends in Immunology. 22 (10): 533–536. doi:10.1016/S1471-4906(01)02034-8. ISSN 1471-4906. PMID 11574261.
  12. Mulero, Julio J.; Nelken, Sarah T.; Ford, J. E. (2000-05-01). "Organization of the human interleukin-1 receptor antagonist gene IL1HY1". Immunogenetics. 51 (6): 425–428. doi:10.1007/s002510050640. ISSN 1432-1211. PMID 10866108. S2CID 37207859.
  13. Busfield, S. J.; Comrack, C. A.; Yu, G.; Chickering, T. W.; Smutko, J. S.; Zhou, H.; Leiby, K. R.; Holmgren, L. M.; Gearing, D. P.; Pan, Y. (2000-06-01). "Identification and Gene Organization of Three Novel Members of the IL-1 Family on Human Chromosome 2". Genomics. 66 (2): 213–216. doi:10.1006/geno.2000.6184. ISSN 0888-7543. PMID 10860666.
  14. Meier-Schiesser, Barbara; Feldmeyer, Laurence; Jankovic, Dragana; Mellett, Mark; Satoh, Takashi K.; Yerly, Daniel; Navarini, Alexander; Abe, Riichiro; Yawalkar, Nikhil; Chung, Wen-Hung; French, Lars E.; Contassot, Emmanuel (2019-04-01). "Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis". Journal of Investigative Dermatology. 139 (4): 848–858. doi:10.1016/j.jid.2018.10.023. ISSN 0022-202X. PMID 30395846. S2CID 53234390.
  15. Neurath, Markus F. (2020-10-01). "IL-36 in chronic inflammation and cancer". Cytokine & Growth Factor Reviews. 55: 70–79. doi:10.1016/j.cytogfr.2020.06.006. ISSN 1359-6101. PMID 32540133. S2CID 219706469.
  16. Sehat, Mojtaba; Talaei, Rezvan; Dadgostar, Ehsan; Nikoueinejad, Hassan; Akbari, Hossein (2018-04-28). "Evaluating Serum Levels of IL-33, IL-36, IL-37 and Gene Expression of IL-37 in Patients with Psoriasis Vulgaris". Iranian Journal of Allergy, Asthma and Immunology. 17 (2): 179–187. ISSN 1735-5249. PMID 29757591.
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