Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6MW31)

• DOT Name: Interleukin-1 receptor-like 1 (IL1RL1)
• Synonyms: EC 3.2.2.6; Protein ST2
• Gene Name: IL1RL1
• UniProt ID: ILRL1_HUMAN
• PDB ID: 4KC3
• EC Number: 3.2.2.6
• Pfam ID: PF07679 ; PF01582
• Sequence:
  MGFWILAILTILMYSTAAKFSKQSWGLENEALIVRCPRQGKPSYTVDWYYSQTNKSIPTQ
  ERNRVFASGQLLKFLPAAVADSGIYTCIVRSPTFNRTGYANVTIYKKQSDCNVPDYLMYS
  TVSGSEKNSKIYCPTIDLYNWTAPLEWFKNCQALQGSRYRAHKSFLVIDNVMTEDAGDYT
  CKFIHNENGANYSVTATRSFTVKDEQGFSLFPVIGAPAQNEIKEVEIGKNANLTCSACFG
  KGTQFLAAVLWQLNGTKITDFGEPRIQQEEGQNQSFSNGLACLDMVLRIADVKEEDLLLQ
  YDCLALNLHGLRRHTVRLSRKNPIDHHSIYCIIAVCSVFLMLINVLVIILKMFWIEATLL
  WRDIAKPYKTRNDGKLYDAYVVYPRNYKSSTDGASRVEHFVHQILPDVLENKCGYTLCIY
  GRDMLPGEDVVTAVETNIRKSRRHIFILTPQITHNKEFAYEQEVALHCALIQNDAKVILI
  EMEALSELDMLQAEALQDSLQHLMKVQGTIKWREDHIANKRSLNSKFWKHVRYQMPVPSK
  IPRKASSLTPLAAQKQ
• Function: Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP. Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function (Probable). Upon tissue injury, induces UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages; [Isoform B]: Inhibits IL-33 signaling.
• Tissue Specificity: Highly expressed in kidney, lung, placenta, stomach, skeletal muscle, colon and small intestine. Isoform A is prevalently expressed in the lung, testis, placenta, stomach and colon. Isoform B is more abundant in the brain, kidney and the liver. Isoform C is not detected in brain, heart, liver, kidney and skeletal muscle. Expressed on T-cells in fibrotic liver; at protein level. Overexpressed in fibrotic and cirrhotic liver.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway:
  (Name not found)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phencyclidine	DMQBEYX	Investigative	Interleukin-1 receptor-like 1 (IL1RL1) increases the response to substance of Phencyclidine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[9]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[5]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Interleukin-1 receptor-like 1 (IL1RL1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interleukin-1 receptor-like 1 (IL1RL1).	[11]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [6] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [7] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [9] 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.
• [10] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 2010 Jan-Feb;24(1):10-20.
• [11] 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.
• [12] IL-33/ST2 signaling modulates Afghanistan particulate matter induced airway hyperresponsiveness in mice. Toxicol Appl Pharmacol. 2020 Oct 1;404:115186. doi: 10.1016/j.taap.2020.115186. Epub 2020 Aug 8.