Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-27 receptor subunit alpha (IL27RA)
• Synonyms: IL-27 receptor subunit alpha; IL-27R subunit alpha; IL-27R-alpha; IL-27RA; Cytokine receptor WSX-1; Cytokine receptor-like 1; Type I T-cell cytokine receptor; TCCR; ZcytoR1
• Gene Name: IL27RA
• Related Disease:
  Mast cell neoplasm
  Spondyloarthropathy
  Acute graft versus host disease
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Autoimmune disease
  Endometrial carcinoma
  Melanoma
  Pneumoconiosis
  Pneumonia
  Pneumonitis
  Tuberculosis
  Age-related macular degeneration
  Nasopharyngeal carcinoma
  Acute myelogenous leukaemia
  Myeloproliferative neoplasm
  Nervous system inflammation
  Prune belly syndrome
  Rheumatoid arthritis
• UniProt ID: I27RA_HUMAN
• PDB ID: 7T5M; 7U7N; 8D85
• Pfam ID: PF00041
• Sequence:
  MRGGRGAPFWLWPLPKLALLPLLWVLFQRTRPQGSAGPLQCYGVGPLGDLNCSWEPLGDL
  GAPSELHLQSQKYRSNKTQTVAVAAGRSWVAIPREQLTMSDKLLVWGTKAGQPLWPPVFV
  NLETQMKPNAPRLGPDVDFSEDDPLEATVHWAPPTWPSHKVLICQFHYRRCQEAAWTLLE
  PELKTIPLTPVEIQDLELATGYKVYGRCRMEKEEDLWGEWSPILSFQTPPSAPKDVWVSG
  NLCGTPGGEEPLLLWKAPGPCVQVSYKVWFWVGGRELSPEGITCCCSLIPSGAEWARVSA
  VNATSWEPLTNLSLVCLDSASAPRSVAVSSIAGSTELLVTWQPGPGEPLEHVVDWARDGD
  PLEKLNWVRLPPGNLSALLPGNFTVGVPYRITVTAVSASGLASASSVWGFREELAPLVGP
  TLWRLQDAPPGTPAIAWGEVPRHQLRGHLTHYTLCAQSGTSPSVCMNVSGNTQSVTLPDL
  PWGPCELWVTASTIAGQGPPGPILRLHLPDNTLRWKVLPGILFLWGLFLLGCGLSLATSG
  RCYHLRHKVLPRWVWEKVPDPANSSSGQPHMEQVPEAQPLGDLPILEVEEMEPPPVMESS
  QPAQATAPLDSGYEKHFLPTPEELGLLGPPRPQVLA
• Function: Receptor for IL27. Requires IL6ST/GP130 to mediate signal transduction in response to IL27. This signaling system acts through STAT3 and STAT1. Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and CNTFR. Involved in the regulation of Th1-type immune responses. Also appears to be involved in innate defense mechanisms.
• Tissue Specificity: Highly expressed in lymphoid tissues such as spleen, lymph nodes and peripheral blood leukocytes. Weakly expressed in other tissues examined including heart, brain, fetal and adult lung, liver, skeletal muscle, kidney, pancreas, prostate, testis, ovary, small intestine, kidney and colon. In the lymphoid system, higher level expression in CD4+ T-cell subsets than in CD8+ T-cell subsets. Also weaker expression in CD19+ B-cells and monocytes.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  Th17 cell differentiation (hsa04659)
• Reactome Pathway:
  Interleukin-27 signaling (R-HSA-9020956)
  Interleukin-35 Signalling (R-HSA-8984722)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mast cell neoplasm	DIS6NFMB	Definitive	Altered Expression	[1]
Spondyloarthropathy	DISBPYCZ	Definitive	Biomarker	[2]
Acute graft versus host disease	DIS8KLVM	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Asthma	DISW9QNS	Strong	Genetic Variation	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[8]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Pneumoconiosis	DISSJLBN	Strong	Biomarker	[11]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[7]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[12]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[13]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[14]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[15]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[15]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[16]
Prune belly syndrome	DISBIBMN	Limited	Genetic Variation	[17]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Interleukin-27 receptor subunit alpha (IL27RA) affects the response to substance of Fluorouracil.	[38]

20 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-27 receptor subunit alpha (IL27RA).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[26]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[30]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[31]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[30]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interleukin-27 receptor subunit alpha (IL27RA).	[37]

References

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• [2] A spontaneous model of spondyloarthropathies that develops bone loss and pathological bone formation: A process regulated by IL27RA-/- and mutant-p53.PLoS One. 2018 Mar 1;13(3):e0193485. doi: 10.1371/journal.pone.0193485. eCollection 2018.
• [3] Soluble interleukin-27 receptor alpha is a valuable prognostic biomarker for acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.Sci Rep. 2018 Jul 9;8(1):10328. doi: 10.1038/s41598-018-28614-4.
• [4] Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells.Oncoimmunology. 2017 Jan 20;6(2):e1268309. doi: 10.1080/2162402X.2016.1268309. eCollection 2017.
• [5] SH3-binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide humanin by inhibiting c-Jun NH2-terminal kinase.J Biol Chem. 2013 Aug 23;288(34):24691-704. doi: 10.1074/jbc.M113.469692. Epub 2013 Jul 16.
• [6] IL-27R signaling controls myeloid cells accumulation and antigen-presentation in atherosclerosis.Sci Rep. 2017 May 23;7(1):2255. doi: 10.1038/s41598-017-01828-8.
• [7] Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population.J Hum Genet. 2007;52(4):355-361. doi: 10.1007/s10038-007-0123-8. Epub 2007 Feb 22.
• [8] Treg-specific IL-27R deletion uncovers a key role for IL-27 in Treg function to control autoimmunity.Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10190-10195. doi: 10.1073/pnas.1703100114. Epub 2017 Sep 5.
• [9] Rapamycin Synergizes with Cisplatin in Antiendometrial Cancer Activation by Improving IL-27-Stimulated Cytotoxicity of NK Cells.Neoplasia. 2018 Jan;20(1):69-79. doi: 10.1016/j.neo.2017.11.003. Epub 2017 Dec 1.
• [10] Antiproliferative activity of IL-27 on melanoma.J Immunol. 2008 May 15;180(10):6527-35. doi: 10.4049/jimmunol.180.10.6527.
• [11] Pathway analysis for a genome-wide association study of pneumoconiosis.Toxicol Lett. 2015 Jan 5;232(1):284-92. doi: 10.1016/j.toxlet.2014.10.028. Epub 2014 Nov 4.
• [12] The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells.Mucosal Immunol. 2018 Jul;11(4):1168-1180. doi: 10.1038/s41385-018-0026-3. Epub 2018 May 4.
• [13] TCCR/WSX-1 is a novel angiogenic factor in age-related macular degeneration.Mol Vis. 2012;18:234-40. Epub 2012 Jan 28.
• [14] Down-regulation of gp130 in nasopharyngeal carcinoma.Am J Rhinol Allergy. 2009 Jan-Feb;23(1):28-32. doi: 10.2500/ajra.2009.23.3257.
• [15] Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor.Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18502-7. doi: 10.1073/pnas.0702388104. Epub 2007 Nov 14.
• [16] Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells.Front Immunol. 2017 Oct 27;8:1392. doi: 10.3389/fimmu.2017.01392. eCollection 2017.
• [17] IL-27 signaling deficiency develops Th17-enhanced Th2-dominant inflammation in murine allergic conjunctivitis model.Allergy. 2019 May;74(5):910-921. doi: 10.1111/all.13691. Epub 2019 Jan 4.
• [18] Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis.Arthritis Res Ther. 2010;12(4):R129. doi: 10.1186/ar3067. Epub 2010 Jul 6.
• [19] 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.
• [20] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [24] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [27] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [28] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [29] 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.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [32] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [33] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [34] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [35] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [36] 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.
• [37] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [38] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.