Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWWWK45)

• DOT Name: Interferon lambda receptor 1 (IFNLR1)
• Synonyms: IFN-lambda receptor 1; IFN-lambda-R1; Cytokine receptor class-II member 12; Cytokine receptor family 2 member 12; CRF2-12; Interleukin-28 receptor subunit alpha; IL-28 receptor subunit alpha; IL-28R-alpha; IL-28RA; Likely interleukin or cytokine receptor 2; LICR2
• Gene Name: IFNLR1
• Related Disease:
  Acute myocardial infarction
  Advanced cancer
  Breast cancer
  Cryohydrocytosis
  Hepatitis B virus infection
  Hepatitis C virus infection
  Herpes simplex encephalitis
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Osteoarthritis
  Palmoplantar pustulosis
  Psoriasis
  Psoriatic arthritis
  Rhinitis
  Sjogren syndrome
  Systemic lupus erythematosus
  Vitiligo
  Pancreatic cancer
  Bronchiolitis
  Rheumatoid arthritis
• UniProt ID: INLR1_HUMAN
• PDB ID: 3OG4; 3OG6; 5IXD; 5IXI; 5L04; 5T5W
• Pfam ID: PF01108
• Sequence:
  MAGPERWGPLLLCLLQAAPGRPRLAPPQNVTLLSQNFSVYLTWLPGLGNPQDVTYFVAYQ
  SSPTRRRWREVEECAGTKELLCSMMCLKKQDLYNKFKGRVRTVSPSSKSPWVESEYLDYL
  FEVEPAPPVLVLTQTEEILSANATYQLPPCMPPLDLKYEVAFWKEGAGNKTLFPVTPHGQ
  PVQITLQPAASEHHCLSARTIYTFSVPKYSKFSKPTCFLLEVPEANWAFLVLPSLLILLL
  VIAAGGVIWKTLMGNPWFQRAKMPRALDFSGHTHPVATFQPSRPESVNDLFLCPQKELTR
  GVRPTPRVRAPATQQTRWKKDLAEDEEEEDEEDTEDGVSFQPYIEPPSFLGQEHQAPGHS
  EAGGVDSGRPRAPLVPSEGSSAWDSSDRSWASTVDSSWDRAGSSGYLAEKGPGQGPGGDG
  HQESLPPPEFSKDSGFLEELPEDNLSSWATWGTLPPEPNLVPGGPPVSLQTLTFCWESSP
  EEEEEARESEIEDSDAGSWGAESTQRTEDRGRTLGHYMAR
• Function: The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state. Determines the cell type specificity of the lambda interferon action. Shows a more restricted pattern of expression in the epithelial tissues thereby limiting responses to lambda interferons primarily to epithelial cells of the respiratory, gastrointestinal, and reproductive tracts. Seems not to be essential for early virus-activated host defense in vaginal infection, but plays an important role in Toll-like receptor (TLR)-induced antiviral defense. Plays a significant role in the antiviral immune defense in the intestinal epithelium.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway:
  Interleukin-20 family signaling (R-HSA-8854691)
  Other interleukin signaling (R-HSA-449836)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Cryohydrocytosis	DISMQHL3	Strong	Altered Expression	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[5]
Herpes simplex encephalitis	DISGX28I	Strong	Genetic Variation	[6]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[8]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[9]
Palmoplantar pustulosis	DISCNSWD	Strong	Biomarker	[10]
Psoriasis	DIS59VMN	Strong	Biomarker	[11]
Psoriatic arthritis	DISLWTG2	Strong	Genetic Variation	[12]
Rhinitis	DISKLMN7	Strong	Genetic Variation	[13]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[14]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[15]
Vitiligo	DISR05SL	Strong	Biomarker	[16]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[17]
Bronchiolitis	DISEE9BG	Limited	Altered Expression	[18]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Interferon lambda receptor 1 (IFNLR1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Interferon lambda receptor 1 (IFNLR1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Interferon lambda receptor 1 (IFNLR1).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Interferon lambda receptor 1 (IFNLR1).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interferon lambda receptor 1 (IFNLR1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Interferon lambda receptor 1 (IFNLR1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Interferon lambda receptor 1 (IFNLR1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interferon lambda receptor 1 (IFNLR1).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon lambda receptor 1 (IFNLR1).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Interferon lambda receptor 1 (IFNLR1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon lambda receptor 1 (IFNLR1).	[29]

References

• [1] Protective effects of IL28RA siRNA on cardiomyocytes in hypoxia/reoxygenation injury.Anatol J Cardiol. 2017 Sep;18(3):168-174. doi: 10.14744/AnatolJCardiol.2017.7763. Epub 2017 Jun 22.
• [2] Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3.Int J Mol Med. 2010 May;25(5):807-12.
• [3] IFN- receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-3 genotype and with nonresponsiveness to IFN- therapies.J Exp Med. 2014 May 5;211(5):857-68. doi: 10.1084/jem.20131557. Epub 2014 Apr 21.
• [4] Role of Functional IFNL4, IFNLR1, IFNA, IFNAR2 Polymorphisms in Hepatitis B virus-related liver disease in Han Chinese population.J Viral Hepat. 2018 Mar;25(3):306-313. doi: 10.1111/jvh.12817. Epub 2017 Nov 29.
• [5] Zinc is a potent and specific inhibitor of IFN-3 signalling.Nat Commun. 2017 May 17;8:15245. doi: 10.1038/ncomms15245.
• [6] Frequently used bioinformatics tools overestimate the damaging effect of allelic variants.Genes Immun. 2019 Jan;20(1):10-22. doi: 10.1038/s41435-017-0002-z. Epub 2017 Dec 4.
• [7] Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing inMice With Colitis and Is Increased in Mucosa of Patients WithInflammatory Bowel Disease.Gastroenterology. 2017 Jul;153(1):123-138.e8. doi: 10.1053/j.gastro.2017.03.015. Epub 2017 Mar 23.
• [8] Analysis of the IL28RA locus as genetic risk factor for multiple sclerosis.J Neuroimmunol. 2012 Apr;245(1-2):98-101. doi: 10.1016/j.jneuroim.2012.02.005. Epub 2012 Mar 2.
• [9] Interleukin-29 Enhances Synovial Inflammation and Cartilage Degradation in Osteoarthritis.Mediators Inflamm. 2016;2016:9631510. doi: 10.1155/2016/9631510. Epub 2016 Jun 28.
• [10] A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.Nat Genet. 2010 Nov;42(11):985-90. doi: 10.1038/ng.694. Epub 2010 Oct 17.
• [11] IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression.Mol Biol Rep. 2019 Feb;46(1):1189-1197. doi: 10.1007/s11033-019-04586-0. Epub 2019 Jan 10.
• [12] Investigation of 20 non-HLA (human leucocyte antigen) psoriasis susceptibility loci in Chinese patients with psoriatic arthritis and psoriasis vulgaris.Br J Dermatol. 2013 May;168(5):1060-5. doi: 10.1111/bjd.12142.
• [13] Analysis of the variations in IL-28RA gene and their association with allergic rhinitis.Exp Mol Med. 2006 Jun 30;38(3):302-9. doi: 10.1038/emm.2006.36.
• [14] Expression of type III interferons (IFNs) and their receptor in Sjgren's syndrome.Clin Exp Immunol. 2016 Dec;186(3):304-312. doi: 10.1111/cei.12865. Epub 2016 Oct 4.
• [15] Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population.J Med Genet. 2013 Dec;50(12):812-8. doi: 10.1136/jmedgenet-2013-101787. Epub 2013 Sep 26.
• [16] The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells.Hum Immunol. 2012 Apr;73(4):393-8. doi: 10.1016/j.humimm.2012.01.011. Epub 2012 Jan 31.
• [17] Significance of IL28RA in diagnosis of early pancreatic cancer and its regulation to pancreatic cancer cells by JAK/STAT signaling pathway - effects of IL28RA on pancreatic cancer.Eur Rev Med Pharmacol Sci. 2019 Nov;23(22):9863-9870. doi: 10.26355/eurrev_201911_19550.
• [18] Interferon lambda receptor 1 (IFNL1R) transcript is highly expressed in rhinovirus bronchiolitis and correlates with disease severity.J Clin Virol. 2018 May;102:101-109. doi: 10.1016/j.jcv.2018.03.003. Epub 2018 Mar 10.
• [19] IL-29 enhances Toll-like receptor-mediated IL-6 and IL-8 production by the synovial fibroblasts from rheumatoid arthritis patients.Arthritis Res Ther. 2013 Oct 29;15(5):R170. doi: 10.1186/ar4357.
• [20] 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.
• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] 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.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [27] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.