Interleukin 36

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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]

Contents

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 2 q14.1. [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] 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. [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. [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 it's levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful biomarkers in patients with psoriasis. [17]

Related Research Articles

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<span class="mw-page-title-main">Interleukin 24</span>

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<span class="mw-page-title-main">Interleukin 22</span>

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

<span class="mw-page-title-main">Interleukin 20</span>

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<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

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<span class="mw-page-title-main">Interleukin 19</span>

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<span class="mw-page-title-main">Interleukin 36 receptor antagonist</span> Protein-coding gene in the species Homo sapiens

Interleukin 36 receptor antagonist (IL-36RA) is a member of the interleukin-36 family of cytokines. It was previously named Interleukin-1 family member 5 (IL1F5).

<span class="mw-page-title-main">Interleukin 37</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">IL36G</span>

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<span class="mw-page-title-main">IL17A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Interleukin-17 receptor</span> Type of protein receptor

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<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

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<span class="mw-page-title-main">IL1RL1</span>

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<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

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<span class="mw-page-title-main">Interleukin 17F</span>

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References

  1. 1 2 3 4 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. 1 2 3 4 5 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. ↑ 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. doi:10.1172/jci.insight.141193. ISSN   2379-3708. PMC   9462487 . PMID   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. 66 (2): 213–216. doi:10.1006/geno.2000.6184. ISSN   0888-7543. PMID   10860666.
  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. 139 (4): 848–858. doi: 10.1016/j.jid.2018.10.023 . ISSN   0022-202X. PMID   30395846. S2CID   53234390.
  16. ↑ 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.
  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): 179–187. ISSN   1735-5249. PMID   29757591.
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