Interleukin 36 receptor antagonist explained

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).^{[1] [2] [3] [4]}

The protein is known to inhibit the effects of Interleukin-36 cytokines (IL-36α, IL-36β and IL-36γ) via competing with their receptor IL-36R/IL1RL2 and thereby inhibiting their proinflammatory effects.^[5]

Roles in disease

Mutations in the IL-36RN gene resulting in a decrease or production of defective IL-36RA protein have been shown to cause inflammatory skin diseases including generalised pustular psoriasis, acrodermatitis continua suppurativa Hallopeau (ACH) and acute generalized exanthematous pustulosis (AGEP).^[6]

Further reading

• Nicklin MJ, Weith A, Duff GW . A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes . Genomics . 19 . 2 . 382–4 . 1994 . 8188271 . 10.1006/geno.1994.1076 .
• Nothwang HG . Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13 . Genomics . 41 . 3 . 370–8 . 1997 . 9169134 . 10.1006/geno.1997.4654 . vanc. Strahm B . Denich D . 3 . Kübler . Matthias . Schwabe . Jenny . Gingrich . Jeffrey C. . Jauch . Anna . Cox . Angela . Nicklin . Martin J.H. .
• Kumar S . Identification and initial characterization of four novel members of the interleukin-1 family . J. Biol. Chem. . 275 . 14 . 10308–14 . 2000 . 10744718 . 10.1074/jbc.275.14.10308 . vanc. McDonnell PC . Lehr R . 3 . Tierney . L . Tzimas . MN . Griswold . DE . Capper . EA . Tal-Singer . R . Wells . GI . free .
• Busfield SJ . Identification and gene organization of three novel members of the IL-1 family on human chromosome 2 . Genomics . 66 . 2 . 213–6 . 2000 . 10860666 . 10.1006/geno.2000.6184 . vanc. Comrack CA . Yu G . 3 . Chickering . T.W. . Smutko . J.S. . Zhou . H. . Leiby . K.R. . Holmgren . L.M. . Gearing . D.P. .
• Mulero JJ, Nelken ST, Ford JE . Organization of the human interleukin-1 receptor antagonist gene IL1HY1 . Immunogenetics . 51 . 6 . 425–8 . 2000 . 10866108 . 10.1007/s002510050640 . 37207859 .
• Barton JL . A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities . Eur. J. Immunol. . 30 . 11 . 3299–308 . 2001 . 11093146 . 10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S . vanc. Herbst R . Bosisio D . 3 . Higgins . Lee . Nicklin . Martin J. H. . free.
• Pan G . IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp . Cytokine . 13 . 1 . 1–7 . 2001 . 11145836 . 10.1006/cyto.2000.0799 . vanc. Risser P . Mao W . 3 . Baldwin . DT . Zhong . AW . Filvaroff . E . Yansura . D . Lewis . L . Eigenbrot . C .
• Lin H . Cloning and characterization of IL-1HY2, a novel interleukin-1 family member . J. Biol. Chem. . 276 . 23 . 20597–602 . 2001 . 11278614 . 10.1074/jbc.M010095200 . vanc. Ho AS . Haley-Vicente D . 3 . Zhang . J . Bernal-Fussell . J . Pace . AM . Hansen . D . Schweighofer . K . Mize . NK . free .
• Debets R . Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2 . J. Immunol. . 167 . 3 . 1440–6 . 2001 . 11466363 . 10.4049/jimmunol.167.3.1440. vanc. Timans JC . Homey B . 3 . Zurawski . S . Sana . TR . Lo . S . Wagner . J . Edwards . G . Clifford . T . free .
• Tazi-Ahnini R . Genetic analysis of the interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction . Eur. J. Immunogenet. . 29 . 1 . 25–30 . 2002 . 11841485 . 10.1046/j.1365-2370.2002.00271.x . vanc. Cox A . McDonagh AJ . 3 . Nicklin . M. J. H. . Di Giovine . F. S. . Timms . J. M. . Messenger . A. G. . Dimitropoulou . P. . Duff . G. W. .
• Nicklin MJ . A sequence-based map of the nine genes of the human interleukin-1 cluster . Genomics . 79 . 5 . 718–25 . 2002 . 11991722 . 10.1006/geno.2002.6751 . vanc. Barton JL . Nguyen M . 3 . Fitzgerald . Michael G . Duff . Gordon W . Kornman . Ken .
• Strausberg RL . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . vanc. Feingold EA . Grouse LH . 3 . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2002PNAS...9916899M . free .
• Clark HF . The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697 . vanc. Gurney AL . Abaya E . 3 . Baker . K . Baldwin . D . Brush . J . Chen . J . Chow . B . Chui . C .
• Zee RY . IL-1 cluster genes and occurrence of post-percutaneous transluminal coronary angioplasty restenosis: a prospective, angiography-based evaluation . Atherosclerosis . 171 . 2 . 259–64 . 2004 . 14644395 . 10.1016/S0021-9150(03)00294-6 . vanc. Fernandez-Ortiz A . Macaya C . 3 . Pintor . Emilio . Fernandez-Cruz . Arturo . Lindpaintner . Klaus .
• Ota T . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . vanc. Suzuki Y . Nishikawa T . 3 . Otsuki . Tetsuji . Sugiyama . Tomoyasu . Irie . Ryotaro . Wakamatsu . Ai . Hayashi . Koji . Sato . Hiroyuki . free .
• Colland F . Functional Proteomics Mapping of a Human Signaling Pathway . Genome Res. . 14 . 7 . 1324–32 . 2004 . 15231748 . 10.1101/gr.2334104 . 442148 . vanc. Jacq X . Trouplin V . 3 . Mougin . C . Groizeleau . C . Hamburger . A . Meil . A . Wojcik . J . Legrain . P .
• Gerhard DS . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . vanc. Wagner L . Feingold EA . 3 . Shenmen . CM . Grouse . LH . Schuler . G . Klein . SL . Old . S . Rasooly . R .
• Macleod . T . Doble . R . McGonagle . D . Wasson . CW . Alase . A . Stacey . M . Wittmann . M . Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist . Scientific Reports . 22 April 2016 . 6 . 24880 . 10.1038/srep24880 . 27101808. 4840362 . 2016NatSR...624880M .

Notes and References

1. Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE . Four new members expand the interleukin-1 superfamily . J Biol Chem . 275 . 2 . 1169–75 . Feb 2000 . 10625660 . 10.1074/jbc.275.2.1169 . free .
2. Mulero JJ, Pace AM, Nelken ST, Loeb DB, Correa TR, Drmanac R, Ford JE . IL1HY1: A novel interleukin-1 receptor antagonist gene . Biochem Biophys Res Commun . 263 . 3 . 702–6 . Nov 1999 . 10512743 . 10.1006/bbrc.1999.1440 .
3. Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, Kastelein RA, Kumar S, Lin H, Mulero JJ, Pan J, Pan Y, Smith DE, Young PR . A new nomenclature for IL-1-family genes . Trends Immunol . 22 . 10 . 536–7 . Sep 2001 . 11574262 . 10.1016/S1471-4906(01)02040-3 .
4. Web site: Entrez Gene: IL36RN interleukin 36 receptor antagonist.
5. Towne. JE. Garka. KE. Renshaw. BR. Virca. GD. Sims. JE. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs.. The Journal of Biological Chemistry. 2 April 2004. 279. 14. 13677–88. 10.1074/jbc.M400117200. 14734551. free.
6. Navarini. AA. Valeyrie-Allanore. L. Setta-Kaffetzi. N. Barker. JN. Capon. F. Creamer. D. Roujeau. JC. Sekula. P. Simpson. MA. Trembath. RC. Mockenhaupt. M. Smith. CH. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis.. The Journal of Investigative Dermatology. July 2013. 133. 7. 1904–7. 10.1038/jid.2013.44. 23358093. free.