Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5CO95A)

• DOT Name: Interleukin-36 receptor antagonist protein (IL36RN)
• Synonyms: IL-36Ra; FIL1 delta; IL-1-related protein 3; IL-1RP3; Interleukin-1 HY1; IL-1HY1; Interleukin-1 delta; IL-1 delta; Interleukin-1 family member 5; IL-1F5; Interleukin-1 receptor antagonist homolog 1; IL-1ra homolog 1; Interleukin-1-like protein 1; IL-1L1
• Gene Name: IL36RN
• Related Disease:
  Alopecia
  Alopecia areata
  Autoinflammatory syndrome
  Autoinflammatory syndrome, familial, Behcet-like 1
  Dermatitis
  Folliculitis
  Gastric cancer
  Generalized pustular psoriasis
  Hepatitis C virus infection
  Hidradenitis suppurativa
  Inflammation
  Inflammatory bowel disease
  Pityriasis rubra pilaris
  Psoriasis
  Psoriasis 14, pustular
  Pustular psoriasis
  Skin disease
  Stomach cancer
  Usher syndrome type 1G
  Achondroplasia
  Acute myelogenous leukaemia
  Keratitis
  Osteoarthritis
  Palmoplantar pustulosis
  Autoimmune disease
  Peptic esophagitis
• UniProt ID: I36RA_HUMAN
• PDB ID: 4P0J; 4P0K; 4P0L
• Pfam ID: PF00340
• Sequence:
  MVLSGALCFRMKDSALKVLYLHNNQLLAGGLHAGKVIKGEEISVVPNRWLDASLSPVILG
  VQGGSQCLSCGVGQEPTLTLEPVNIMELYLGAKESKSFTFYRRDMGLTSSFESAAYPGWF
  LCTVPEADQPVRLTQLPENGGWNAPITDFYFQQCD
• Function: Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor. Proposed to play a role in skin inflammation. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus. May activate an anti-inflammatory signaling pathway by recruiting SIGIRR.
• Tissue Specificity: Predominantly expressed in skin keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Detected also in the spleen, brain leukocyte and macrophage cell types. Increased in lesional psoriasis skin.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Interleukin-36 pathway (R-HSA-9014826)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alopecia	DIS37HU4	Strong	Genetic Variation	[1]
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[1]
Autoinflammatory syndrome	DISCMCGL	Strong	Genetic Variation	[2]
Autoinflammatory syndrome, familial, Behcet-like 1	DISH2UT1	Strong	Genetic Variation	[2]
Dermatitis	DISY5SZC	Strong	Biomarker	[3]
Folliculitis	DIS10XOM	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Generalized pustular psoriasis	DISTSNLR	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Altered Expression	[8]
Inflammation	DISJUQ5T	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[10]
Pityriasis rubra pilaris	DISVC72D	Strong	Genetic Variation	[11]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[12]
Psoriasis 14, pustular	DISL2U2O	Strong	Autosomal recessive	[13]
Pustular psoriasis	DISXOG13	Strong	Biomarker	[14]
Skin disease	DISDW8R6	Strong	Genetic Variation	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Usher syndrome type 1G	DISZFLFA	Strong	Biomarker	[15]
Achondroplasia	DISYWN2O	moderate	Genetic Variation	[16]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[17]
Keratitis	DISMFOEI	moderate	Biomarker	[18]
Osteoarthritis	DIS05URM	moderate	Biomarker	[19]
Palmoplantar pustulosis	DISCNSWD	Supportive	Autosomal dominant	[20]
Autoimmune disease	DISORMTM	Limited	Biomarker	[21]
Peptic esophagitis	DISJSGBZ	Limited	Biomarker	[22]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Interleukin-36 receptor antagonist protein (IL36RN).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-36 receptor antagonist protein (IL36RN).	[28]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-36 receptor antagonist protein (IL36RN).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Interleukin-36 receptor antagonist protein (IL36RN).	[25]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Interleukin-36 receptor antagonist protein (IL36RN).	[26]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Interleukin-36 receptor antagonist protein (IL36RN).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-36 receptor antagonist protein (IL36RN).	[29]

References

• [1] 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. 2002 Feb;29(1):25-30. doi: 10.1046/j.1365-2370.2002.00271.x.
• [2] Coinheritance of generalized pustular psoriasis and familial Behet-like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state.J Dermatol. 2019 Oct;46(10):907-910. doi: 10.1111/1346-8138.15034. Epub 2019 Jul 29.
• [3] The IL-1 family of cytokines. Do they have a role in scleroderma fibrosis?.Immunol Lett. 2018 Mar;195:30-37. doi: 10.1016/j.imlet.2017.11.012. Epub 2017 Dec 5.
• [4] Upregulation of IL-36 cytokines in folliculitis and eosinophilic pustular folliculitis.Australas J Dermatol. 2020 Feb;61(1):e39-e45. doi: 10.1111/ajd.13143. Epub 2019 Aug 19.
• [5] Associations of Il-1 Family-Related Polymorphisms With Gastric Cancer Risk and the Role of Mir-197 In Il-1f5 Expression.Medicine (Baltimore). 2015 Nov;94(47):e1982. doi: 10.1097/MD.0000000000001982.
• [6] Lack of association between mutation in IL36RN and palmoplantar pustular psoriasis in Chinese patients.An Bras Dermatol. 2019 Nov-Dec;94(6):658-663. doi: 10.1016/j.abd.2019.01.008. Epub 2019 Oct 26.
• [7] Monocytes inhibit hepatitis C virus-induced TRAIL expression on CD56(bright) NK cells.J Hepatol. 2017 Dec;67(6):1148-1156. doi: 10.1016/j.jhep.2017.07.028. Epub 2017 Aug 11.
• [8] Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.Br J Dermatol. 2018 Mar;178(3):761-767. doi: 10.1111/bjd.16019. Epub 2018 Jan 31.
• [9] Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011 Sep 9;89(3):432-7. doi: 10.1016/j.ajhg.2011.07.022. Epub 2011 Aug 11.
• [10] Differential Expression of IL-36 Family Members and IL-38 by Immune and Nonimmune Cells in Patients with Active Inflammatory Bowel Disease.Biomed Res Int. 2018 Dec 10;2018:5140691. doi: 10.1155/2018/5140691. eCollection 2018.
• [11] Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin.J Dermatol Sci. 2018 May;90(2):105-111. doi: 10.1016/j.jdermsci.2018.01.012. Epub 2018 Feb 1.
• [12] Immune Control by TRAF6-Mediated Pathways of Epithelial Cells in the EIME (Epithelial Immune Microenvironment).Front Immunol. 2019 May 16;10:1107. doi: 10.3389/fimmu.2019.01107. eCollection 2019.
• [13] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [14] Interleukin (IL)-8 and IL-36 but not IL-36Ra are related to acrosyringia in pustule formation associated with palmoplantar pustulosis.Clin Exp Dermatol. 2019 Jan;44(1):52-57. doi: 10.1111/ced.13689. Epub 2018 Jun 12.
• [15] Identification of stage-specific biomarkers in lung adenocarcinoma based on RNA-seq data.Tumour Biol. 2015 Aug;36(8):6391-9. doi: 10.1007/s13277-015-3327-0. Epub 2015 Apr 11.
• [16] Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis.Dermatology. 2013;226(1):28-31. doi: 10.1159/000346572. Epub 2013 Feb 15.
• [17] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [18] Opposing Effects of IL-1Ra and IL-36Ra on Innate Immune Response to Pseudomonas aeruginosa Infection in C57BL/6 Mouse Corneas.J Immunol. 2018 Jul 15;201(2):688-699. doi: 10.4049/jimmunol.1800046. Epub 2018 Jun 11.
• [19] TGF- type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis.Sci Transl Med. 2019 May 8;11(491):eaan2585. doi: 10.1126/scitranslmed.aan2585.
• [20] Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol. 2013 May;133(5):1366-9. doi: 10.1038/jid.2012.490. Epub 2013 Jan 10.
• [21] Increased serum IL-36 and IL-36 levels in patients with systemic lupus erythematosus: Association with disease activity and arthritis.Int Immunopharmacol. 2018 May;58:103-108. doi: 10.1016/j.intimp.2018.03.011. Epub 2018 Mar 20.
• [22] Association between interleukin-1beta-511C/T polymorphism and reflux esophagitis in Japan.J Gastroenterol. 2005 Sep;40(9):873-7. doi: 10.1007/s00535-005-1672-2.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [25] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [26] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [27] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.