IL36G explained

Interleukin-36 gamma previously known as interleukin-1 family member 9 (IL1F9) is a protein that in humans is encoded by the IL36G gene.^{[1] [2] [3] [4]}

Expression

IL36G is well-expressed in the epithelium of the skin, gut, and lung.^[5] In the skin IL36G is predominantly expressed in epidermal granular layer keratinocytes with little to no expression in basal layer keratinocytes.^[6]

Function

The protein encoded by this gene is a member of the interleukin-1 cytokine family. This gene and eight other interleukin-1 family genes form a cytokine gene cluster on chromosome 2.^[7] The activity of this cytokine is mediated via the interleukin-1 receptor-like 2 (IL1RL2/IL1R-rp2/IL-36 receptor), and is specifically inhibited by interleukin-36 receptor antagonist, (IL-36RA/IL1F5/IL-1 delta). Interferon-gamma, tumor necrosis factor-alpha and interleukin-1 β (IL-1β) are reported to stimulate the expression of this cytokine in keratinocytes. The expression of this cytokine in keratinocytes can also be induced by a multiple Pathogen-Associated Molecular Patterns (PAMPs).^[8] Both IL-36γ mRNA and protein have been linked to psoriasis lesions and has been used as a biomarker for differentiating between eczema and psoriasis.^{[9] [10]} As with many other interleukin-1 family cytokines IL-36γ requires proteolytic cleavage of its N-terminus for full biological activity.^[11] However, unlike IL-1β the activation of IL-36γ is inflammasome-independent. IL-36γ is specifically cleaved by the endogenous protease cathepsin S as well exogenous proteases derived from fungal and bacterial pathogens.^{[12] [13]}

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 . January 1994 . 8188271 . 10.1006/geno.1994.1076 .
• Nothwang HG, Strahm B, Denich D, Kübler M, Schwabe J, Gingrich JC, Jauch A, Cox A, Nicklin MJ, Kurnit DM, Hildebrandt F . 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 . May 1997 . 9169134 . 10.1006/geno.1997.4654 .
• Mulero JJ, Pace AM, Nelken ST, Loeb DB, Correa TR, Drmanac R, Ford JE . IL1HY1: A novel interleukin-1 receptor antagonist gene . Biochemical and Biophysical Research Communications . 263 . 3 . 702–6 . October 1999 . 10512743 . 10.1006/bbrc.1999.1440 .
• Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE . Four new members expand the interleukin-1 superfamily . The Journal of Biological Chemistry . 275 . 2 . 1169–75 . January 2000 . 10625660 . 10.1074/jbc.275.2.1169 . free .
• Barton JL, Herbst R, Bosisio D, Higgins L, Nicklin MJ . 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 . European Journal of Immunology . 30 . 11 . 3299–308 . November 2000 . 11093146 . 10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S . free .
• Pan G, Risser P, Mao W, Baldwin DT, Zhong AW, Filvaroff E, Yansura D, Lewis L, Eigenbrot C, Henzel WJ, Vandlen R . IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp . Cytokine . 13 . 1 . 1–7 . January 2001 . 11145836 . 10.1006/cyto.2000.0799 .
• Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM, Hansen D, Schweighofer K, Mize NK, Ford JE . Cloning and characterization of IL-1HY2, a novel interleukin-1 family member . The Journal of Biological Chemistry . 276 . 23 . 20597–602 . June 2001 . 11278614 . 10.1074/jbc.M010095200 . free .
• Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA . 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 . Journal of Immunology . 167 . 3 . 1440–6 . August 2001 . 11466363 . 10.4049/jimmunol.167.3.1440 . free .
• 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 in Immunology . 22 . 10 . 536–7 . October 2001 . 11574262 . 10.1016/S1471-4906(01)02040-3 .
• 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 . 279 . 14 . 13677–88 . April 2004 . 14734551 . 10.1074/jbc.M400117200 . free .
• Dennis RA, Trappe TA, Simpson P, Carroll C, Huang BE, Nagarajan R, Bearden E, Gurley C, Duff GW, Evans WJ, Kornman K, Peterson CA . Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise . The Journal of Physiology . 560 . Pt 3 . 617–26 . November 2004 . 15331687 . 1665272 . 10.1113/jphysiol.2004.067876 .
• Vos JB, van Sterkenburg MA, Rabe KF, Schalkwijk J, Hiemstra PS, Datson NA . Transcriptional response of bronchial epithelial cells to Pseudomonas aeruginosa: identification of early mediators of host defense . Physiological Genomics . 21 . 3 . 324–36 . May 2005 . 15701729 . 10.1152/physiolgenomics.00289.2004 . 27639384 .

Notes and References

1. Busfield SJ, Comrack CA, Yu G, Chickering TW, Smutko JS, Zhou H, Leiby KR, Holmgren LM, Gearing DP, Pan Y . Identification and gene organization of three novel members of the IL-1 family on human chromosome 2 . Genomics . 66 . 2 . 213–6 . June 2000 . 10860666 . 10.1006/geno.2000.6184 .
2. Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, Capper EA, Tal-Singer R, Wells GI, Doyle ML, Young PR . Identification and initial characterization of four novel members of the interleukin-1 family . The Journal of Biological Chemistry . 275 . 14 . 10308–14 . April 2000 . 10744718 . 10.1074/jbc.275.14.10308 . free .
3. Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K . A sequence-based map of the nine genes of the human interleukin-1 cluster . Genomics . 79 . 5 . 718–25 . May 2002 . 11991722 . 10.1006/geno.2002.6751 .
4. Taylor SL, Renshaw BR, Garka KE, Smith DE, Sims JE . Genomic organization of the interleukin-1 locus . Genomics . 79 . 5 . 726–33 . May 2002 . 11991723 . 10.1006/geno.2002.6752 .
5. Yuan ZC, Xu WD, Liu XY, Liu XY, Huang AF, Su LC . Biology of IL-36 Signaling and Its Role in Systemic Inflammatory Diseases . Frontiers in Immunology . 10 . 2532 . 2019 . 31736959 . 10.3389/fimmu.2019.02532 . 6839525 . free .
6. Merleev A, Ji-Xu A, Toussi A, Tsoi LC, Le ST, Luxardi G, Xing X, Wasikowski R, Liakos W, Brüggen MC, Elder JT, Adamopoulos IE, Izumiya Y, Leal AR, Li Q, Kuzminykh NY, Kirane A, Marusina AI, Gudjonsson JE, Maverakis E . 6 . Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G . JCI Insight . 7 . 16 . August 2022 . 35862195 . 10.1172/jci.insight.141193 . 9462487 .
7. Garlanda C, Dinarello CA, Mantovani A . The interleukin-1 family: back to the future . Immunity . 39 . 6 . 1003–18 . December 2013 . 24332029 . 3933951 . 10.1016/j.immuni.2013.11.010 .
8. Gabay C, Towne JE . Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions . Journal of Leukocyte Biology . 97 . 4 . 645–52 . April 2015 . 25673295 . 10.1189/jlb.3RI1014-495R . 36594830 . free .
9. Berekméri A, Latzko A, Alase A, Macleod T, Ainscough JS, Laws P, Goodfield M, Wright A, Helliwell P, Edward S, Brown GD, Reid DM, Wenzel J, Stacey M, Wittmann M . 6 . Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema . The Journal of Allergy and Clinical Immunology . 142 . 3 . 988–991.e4 . September 2018 . 29782895 . 6127028 . 10.1016/j.jaci.2018.04.031 . 2164/10849 .
10. D'Erme AM, Wilsmann-Theis D, Wagenpfeil J, Hölzel M, Ferring-Schmitt S, Sternberg S, Wittmann M, Peters B, Bosio A, Bieber T, Wenzel J . 6 . IL-36γ (IL-1F9) is a biomarker for psoriasis skin lesions . The Journal of Investigative Dermatology . 135 . 4 . 1025–1032 . April 2015 . 25525775 . 10.1038/jid.2014.532 . free .
11. Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE . 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 . December 2011 . 21965679 . 3234937 . 10.1074/jbc.M111.267922 . free .
12. Ainscough JS, Macleod T, McGonagle D, Brakefield R, Baron JM, Alase A, Wittmann M, Stacey M . 6 . Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ . Proceedings of the National Academy of Sciences of the United States of America . 114 . 13 . E2748–E2757 . March 2017 . 28289191 . 5380102 . 10.1073/pnas.1620954114 . 2017PNAS..114E2748A . free .
13. Macleod T, Ainscough JS, Hesse C, Konzok S, Braun A, Buhl AL, Wenzel J, Bowyer P, Terao Y, Herrick S, Wittmann M, Stacey M . 6 . The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues . Cell Reports . 33 . 11 . 108515 . December 2020 . 33326792 . 10.1016/j.celrep.2020.108515 . 7758160 . free .