Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIS3OF8)

DOT Name Interleukin-27 subunit alpha (IL27)
Synonyms IL-27 subunit alpha; IL-27-A; IL27-A; Interleukin-30; p28
Gene Name IL27
Related Disease
Carcinoma of esophagus ( )
Allergic rhinitis ( )
Arthritis ( )
Autoimmune disease ( )
Bacterial infection ( )
Breast cancer ( )
Breast carcinoma ( )
Cervical cancer ( )
Cervical carcinoma ( )
Chronic obstructive pulmonary disease ( )
Diabetic retinopathy ( )
Epithelial ovarian cancer ( )
Glioma ( )
Hepatitis ( )
Hepatitis A virus infection ( )
Hepatitis C virus infection ( )
Hepatocellular carcinoma ( )
Influenza ( )
Multiple sclerosis ( )
Pleural tuberculosis ( )
Pneumonia ( )
Pneumonitis ( )
Prostate cancer ( )
Prostate neoplasm ( )
Psoriasis ( )
Pulmonary tuberculosis ( )
Rheumatoid arthritis ( )
Systemic lupus erythematosus ( )
Tuberculosis ( )
Uveitis ( )
Ankylosing spondylitis ( )
HIV infectious disease ( )
Lung cancer ( )
Lung carcinoma ( )
Non-small-cell lung cancer ( )
Prostate carcinoma ( )
Colitis ( )
Arteriosclerosis ( )
Asthma ( )
Atherosclerosis ( )
Autoimmune thrombocytopenia ( )
Crohn disease ( )
Hepatitis B virus infection ( )
Immune thrombocytopenia ( )
Inflammatory bowel disease ( )
Melanoma ( )
Nervous system inflammation ( )
Sclerosing cholangitis ( )
Ulcerative colitis ( )
UniProt ID
IL27A_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
7U7N; 7ZXK; 8D85
Sequence
MGQTAGDLGWRLSLLLLPLLLVQAGVWGFPRPPGRPQLSLQELRREFTVSLHLARKLLSE
VRGQAHRFAESHLPGVNLYLLPLGEQLPDVSLTFQAWRRLSDPERLCFISTTLQPFHALL
GGLGTQGRWTNMERMQLWAMRLDLRDLQRHLRFQVLAAGFNLPEEEEEEEEEEEEERKGL
LPGALGSALQGPAQVSWPQLLSTYRLLHSLELVLSRAVRELLLLSKAGHSVWPLGFPTLS
PQP
Function
Associates with EBI3 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR which appears to be required but not sufficient for IL-27-mediated signal transduction. IL-27 potentiate the early phase of TH1 response and suppress TH2 and TH17 differentiation. It induces the differentiation of TH1 cells via two distinct pathways, p38 MAPK/TBX21- and ICAM1/ITGAL/ERK-dependent pathways. It also induces STAT1, STAT3, STAT4 and STAT5 phosphorylation and activates TBX21/T-Bet via STAT1 with resulting IL12RB2 up-regulation, an event crucial to TH1 cell commitment. It suppresses the expression of GATA3, the inhibitor TH1 cells development. In CD8 T-cells, it activates STATs as well as GZMB. IL-27 reveals to be a potent inhibitor of TH17 cell development and of IL-17 production. Indeed IL27 alone is also able to inhibit the production of IL17 by CD4 and CD8 T-cells. While IL-27 suppressed the development of pro-inflammatory Th17 cells via STAT1, it inhibits the development of anti-inflammatory inducible regulatory T-cells, iTreg, independently of STAT1. IL-27 has also an effect on cytokine production, it suppresses pro-inflammatory cytokine production such as IL2, IL4, IL5 and IL6 and activates suppressors of cytokine signaling such as SOCS1 and SOCS3. Apart from suppression of cytokine production, IL-27 also antagonizes the effects of some cytokines such as IL6 through direct effects on T-cells. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines such as IP-10/CXCL10 and MIG/CXCL9. In vein endothelial cells, it induces IRF1/interferon regulatory factor 1 and increase the expression of MHC class II transactivator/CIITA with resulting up-regulation of major histocompatibility complex class II. IL-27 also demonstrates antiviral activity with inhibitory properties on HIV-1 replication.
Tissue Specificity Expressed in monocytes and in placenta.
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 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Carcinoma of esophagus DISS6G4D Definitive Genetic Variation [1]
Allergic rhinitis DIS3U9HN Strong Biomarker [2]
Arthritis DIST1YEL Strong Biomarker [3]
Autoimmune disease DISORMTM Strong Genetic Variation [4]
Bacterial infection DIS5QJ9S Strong Altered Expression [5]
Breast cancer DIS7DPX1 Strong Genetic Variation [6]
Breast carcinoma DIS2UE88 Strong Genetic Variation [6]
Cervical cancer DISFSHPF Strong Biomarker [7]
Cervical carcinoma DIST4S00 Strong Biomarker [7]
Chronic obstructive pulmonary disease DISQCIRF Strong Altered Expression [8]
Diabetic retinopathy DISHGUJM Strong Biomarker [9]
Epithelial ovarian cancer DIS56MH2 Strong Genetic Variation [1]
Glioma DIS5RPEH Strong Biomarker [10]
Hepatitis DISXXX35 Strong Biomarker [11]
Hepatitis A virus infection DISUMFQV Strong Biomarker [11]
Hepatitis C virus infection DISQ0M8R Strong Biomarker [12]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [13]
Influenza DIS3PNU3 Strong Altered Expression [14]
Multiple sclerosis DISB2WZI Strong Biomarker [15]
Pleural tuberculosis DISD09EG Strong Biomarker [16]
Pneumonia DIS8EF3M Strong Biomarker [11]
Pneumonitis DIS88E0K Strong Biomarker [11]
Prostate cancer DISF190Y Strong Biomarker [17]
Prostate neoplasm DISHDKGQ Strong Biomarker [18]
Psoriasis DIS59VMN Strong Biomarker [19]
Pulmonary tuberculosis DIS6FLUM Strong Genetic Variation [20]
Rheumatoid arthritis DISTSB4J Strong Biomarker [15]
Systemic lupus erythematosus DISI1SZ7 Strong Biomarker [21]
Tuberculosis DIS2YIMD Strong Biomarker [22]
Uveitis DISV0RYS Strong Altered Expression [23]
Ankylosing spondylitis DISRC6IR moderate Genetic Variation [24]
HIV infectious disease DISO97HC moderate Genetic Variation [25]
Lung cancer DISCM4YA moderate Biomarker [26]
Lung carcinoma DISTR26C moderate Biomarker [26]
Non-small-cell lung cancer DIS5Y6R9 moderate Biomarker [26]
Prostate carcinoma DISMJPLE moderate Biomarker [17]
Colitis DISAF7DD Disputed Biomarker [27]
Arteriosclerosis DISK5QGC Limited Genetic Variation [28]
Asthma DISW9QNS Limited Biomarker [29]
Atherosclerosis DISMN9J3 Limited Genetic Variation [28]
Autoimmune thrombocytopenia DISNF0OI Limited Altered Expression [30]
Crohn disease DIS2C5Q8 Limited Genetic Variation [31]
Hepatitis B virus infection DISLQ2XY Limited Biomarker [32]
Immune thrombocytopenia DISVCBNS Limited Altered Expression [30]
Inflammatory bowel disease DISGN23E Limited Biomarker [27]
Melanoma DIS1RRCY Limited Altered Expression [33]
Nervous system inflammation DISB3X5A Limited Biomarker [34]
Sclerosing cholangitis DIS7GZNB Limited Genetic Variation [24]
Ulcerative colitis DIS8K27O Limited Genetic Variation [35]
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⏷ Show the Full List of 49 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
1 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-27 subunit alpha (IL27). [36]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Simvastatin DM30SGU Approved Simvastatin increases the expression of Interleukin-27 subunit alpha (IL27). [37]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Interleukin-27 subunit alpha (IL27). [38]
Nickel chloride DMI12Y8 Investigative Nickel chloride increases the expression of Interleukin-27 subunit alpha (IL27). [39]
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References

1 Common Polymorphisms in IL-27 Genes May Contribute to Risk of Various Human Diseases in Asian Populations: A Meta-Analysis.Med Sci Monit. 2016 Mar 7;22:766-75. doi: 10.12659/msm.895558.
2 Interleukin-27 inhibits helper T cell type-2 response in allergic rhinitis.Auris Nasus Larynx. 2020 Feb;47(1):84-89. doi: 10.1016/j.anl.2019.05.005. Epub 2019 May 30.
3 IL-27: a double agent in the IL-6 family.Clin Exp Immunol. 2018 Jul;193(1):37-46. doi: 10.1111/cei.13116. Epub 2018 Mar 9.
4 Association of single-nucleotide polymorphisms in the IL27 gene with autoimmune thyroid diseases.Endocr Connect. 2019 Mar 1;8(3):173-181. doi: 10.1530/EC-18-0370.
5 Murine myeloid-derived suppressor cells are a source of elevated levels of interleukin-27 in early life and compromise control of bacterial infection.Immunol Cell Biol. 2019 May;97(5):445-456. doi: 10.1111/imcb.12224. Epub 2019 Feb 8.
6 IL-27 -964A>G polymorphism and the risk of breast cancer: a case-control study.Tumour Biol. 2014 Dec;35(12):12099-102. doi: 10.1007/s13277-014-2512-x. Epub 2014 Aug 22.
7 A novel microRNA, hsa-miR-6852 differentially regulated by Interleukin-27 induces necrosis in cervical cancer cells by downregulating the FoxM1 expression.Sci Rep. 2018 Jan 17;8(1):900. doi: 10.1038/s41598-018-19259-4.
8 Bacterial load and inflammatory response in sputum of alpha-1 antitrypsin deficiency patients with COPD.Int J Chron Obstruct Pulmon Dis. 2019 Aug 21;14:1879-1893. doi: 10.2147/COPD.S207203. eCollection 2019.
9 IL-27 regulates HIF-1-mediated VEGFA response in macrophages of diabetic retinopathy patients and healthy individuals.Cytokine. 2019 Jan;113:238-247. doi: 10.1016/j.cyto.2018.07.011. Epub 2018 Jul 13.
10 Molecular screening and genetic diversity analysis of anticancer Azurin-encoding and Azurin-like genes in human gut microbiome deduced through cultivation-dependent and cultivation-independent studies.Int Microbiol. 2019 Dec;22(4):437-449. doi: 10.1007/s10123-019-00070-8. Epub 2019 Mar 20.
11 Murine -Herpesvirus 68 Induces Severe Lung Inflammation in IL-27-Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin.J Immunol. 2018 Apr 15;200(8):2703-2713. doi: 10.4049/jimmunol.1700412. Epub 2018 Mar 2.
12 Impact of IL-27p28 (rs153109) and TNF- (rs1800629) Genetic Polymorphisms on the Progression of HCV Infection in Egyptian Patients.Immunol Invest. 2019 Apr;48(3):255-267. doi: 10.1080/08820139.2018.1510958. Epub 2018 Sep 11.
13 The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by -PD-L1 or -IL6 antibodies.J Leukoc Biol. 2018 Nov;104(5):969-985. doi: 10.1002/JLB.MA1217-495R. Epub 2018 Jul 24.
14 Identification of Amino Acid Residues in Influenza A Virus PA-X That Contribute to Enhanced Shutoff Activity.Front Microbiol. 2019 Mar 6;10:432. doi: 10.3389/fmicb.2019.00432. eCollection 2019.
15 The IL-12 cytokine family in cardiovascular diseases.Cytokine. 2019 Oct;122:154188. doi: 10.1016/j.cyto.2017.10.010. Epub 2017 Oct 23.
16 Biomarkers in the diagnosis of pleural diseases: a 2018 update.Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618808660. doi: 10.1177/1753466618808660.
17 Poly(I:C)-Mediated Death of Human Prostate Cancer Cell Lines Is Induced by Interleukin-27 Treatment.J Interferon Cytokine Res. 2019 Aug;39(8):483-494. doi: 10.1089/jir.2018.0166. Epub 2019 Apr 22.
18 Interleukin-27 expression modifies prostate cancer cell crosstalk with bone and immune cells in vitro.J Cell Physiol. 2013 May;228(5):1127-36. doi: 10.1002/jcp.24265.
19 The IL-23p19/EBI3 heterodimeric cytokine termed IL-39 remains a theoretical cytokine in man.Inflamm Res. 2019 Jun;68(6):423-426. doi: 10.1007/s00011-019-01235-x. Epub 2019 Apr 13.
20 Association between polymorphisms of cytokine genes and secretion of IL-12p70, IL-18, and IL-27 by dendritic cells in patients with pulmonary tuberculosis.Tuberculosis (Edinb). 2019 Mar;115:56-62. doi: 10.1016/j.tube.2019.02.003. Epub 2019 Feb 6.
21 The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus.J Leukoc Biol. 2019 Oct;106(4):967-975. doi: 10.1002/JLB.3AB0518-180RR. Epub 2019 Jun 19.
22 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.
23 Decreased interleukin 27 expression is associated with active uveitis in Behet's disease.Arthritis Res Ther. 2014 May 28;16(3):R117. doi: 10.1186/ar4570.
24 Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
25 Association of interleukin-27 gene polymorphisms with susceptibility to HIV infection and disease progression.J Cell Mol Med. 2019 Apr;23(4):2410-2418. doi: 10.1111/jcmm.14067. Epub 2019 Jan 10.
26 IL-27 inhibits non-small-cell lung cancer cell metastasis by miR-935 in vitro.Onco Targets Ther. 2019 Feb 21;12:1447-1454. doi: 10.2147/OTT.S173207. eCollection 2019.
27 Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10-Dependent, T-Cell-Independent Attenuation of Colonic Mucosal Innate Immune Responses.Inflamm Bowel Dis. 2017 Nov;23(11):1983-1995. doi: 10.1097/MIB.0000000000001274.
28 Interleukin 27 polymorphisms, their association with insulin resistance and their contribution to subclinical atherosclerosis. The GEA Mexican study.Cytokine. 2019 Feb;114:32-37. doi: 10.1016/j.cyto.2018.11.028. Epub 2018 Dec 26.
29 Preventative tracheal administration of interleukin-27 attenuates allergic asthma by improving the lung Th1 microenvironment.J Cell Physiol. 2019 May;234(5):6642-6653. doi: 10.1002/jcp.27422. Epub 2018 Oct 26.
30 Increased interleukin-27 promotes Th1 differentiation in patients with chronic immune thrombocytopenia.Scand J Immunol. 2014 Oct;80(4):276-82. doi: 10.1111/sji.12197.
31 A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals.J Crohns Colitis. 2019 Apr 26;13(5):648-658. doi: 10.1093/ecco-jcc/jjy197.
32 Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication.Cell Mol Immunol. 2018 Mar;15(3):272-281. doi: 10.1038/cmi.2016.67. Epub 2017 Feb 13.
33 Calpain-dependent clearance of the autophagy protein p62/SQSTM1 is a contributor to PK oncolytic activity in melanoma.Gene Ther. 2014 Apr;21(4):371-8. doi: 10.1038/gt.2014.6. Epub 2014 Feb 20.
34 Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3-Dependent but IL-10-Independent Mechanisms In Vivo.J Immunol. 2019 Mar 15;202(6):1680-1685. doi: 10.4049/jimmunol.1800898. Epub 2019 Jan 30.
35 Functional variant in the promoter region of IL-27 alters gene transcription and confers a risk for ulcerative colitis in northern Chinese Han.Hum Immunol. 2017 Mar;78(3):287-293. doi: 10.1016/j.humimm.2017.01.002. Epub 2017 Jan 6.
36 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.
37 Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008 May 15;180(10):6988-96. doi: 10.4049/jimmunol.180.10.6988.
38 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.
39 IL-27 Production and Regulation in Human Dendritic Cells Treated with the Chemical Sensitizer NiSO(4). Chem Res Toxicol. 2018 Dec 17;31(12):1323-1331. doi: 10.1021/acs.chemrestox.8b00203. Epub 2018 Nov 27.