Interleukin 36 Explained

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.

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. IL-36 has also been linked to psoriatic arthritis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and Sjögren's syndrome.

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.

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. In the epidermis IL-36 cytokine expression is limited to granular layer keratinocytes with little to no expression in basal layer keratinocytes.[13]

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).[14]

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.

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.[15]

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.[16]

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 its levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful biomarkers in patients with psoriasis.[17]

Notes and 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 . 10.18632/oncotarget.22814 . 5788690 . 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 . 10.1074/jbc.M117.805739 . 5767850 . 29180446. free .
  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 . 10.1074/jbc.M111.267922 . 3234937 . 21965679. free .
  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 . en . 279 . 14 . 13677–13688 . 10.1074/jbc.M400117200 . 14734551 . 0021-9258. free .
  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 . 10.1182/blood-2012-06-439026 . 22968459 . free.
  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 . 10.1016/j.smim.2013.11.003 . 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 . en . 9 . 3 . 378 . 10.1038/s41419-018-0385-4 . 29515113 . 5841435 . 2041-4889.
  8. Web site: IL36A interleukin 36 alpha [Homo sapiens (human)] - Gene - NCBI ]. 2022-09-09 . www.ncbi.nlm.nih.gov.
  9. Web site: IL36B interleukin 36 beta [Homo sapiens (human)] - Gene - NCBI ]. 2022-09-09 . www.ncbi.nlm.nih.gov.
  10. Web site: IL36G interleukin 36 gamma [Homo sapiens (human)] - Gene - NCBI ]. 2022-09-09 . www.ncbi.nlm.nih.gov.
  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 . en . 22 . 10 . 533–536 . 10.1016/S1471-4906(01)02034-8 . 11574261 . 1471-4906.
  12. Mulero . Julio J. . Nelken . Sarah T. . Ford . J. E. . 2000-05-01 . Organization of the human interleukin-1 receptor antagonist gene IL1HY1 . Immunogenetics . en . 51 . 6 . 425–428 . 10.1007/s002510050640 . 10866108 . 37207859 . 1432-1211.
  13. Merleev . Alexander . Ji-Xu . Antonio . Toussi . Atrin . Tsoi . Lam C. . Le . Stephanie T. . Luxardi . Guillaume . Xing . Xianying . Wasikowski . Rachael . Liakos . William . Brüggen . Marie-Charlotte . Elder . James T. . Adamopoulos . Iannis E. . Izumiya . Yoshihiro . Leal . Annie R. . Li . Qinyuan . 2022-08-22 . Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G . JCI Insight . 7 . 16 . e141193 . 10.1172/jci.insight.141193 . 2379-3708 . 9462487 . 35862195.
  14. 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 . en . 66 . 2 . 213–216 . 10.1006/geno.2000.6184 . 10860666 . 0888-7543.
  15. 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 . en . 139 . 4 . 848–858 . 10.1016/j.jid.2018.10.023 . 30395846 . 53234390 . 0022-202X. free .
  16. Neurath . Markus F. . 2020-10-01 . IL-36 in chronic inflammation and cancer . Cytokine & Growth Factor Reviews . en . 55 . 70–79 . 10.1016/j.cytogfr.2020.06.006 . 32540133 . 219706469 . 1359-6101.
  17. 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 . en . 179–187 . 29757591 . 1735-5249.

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