Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4BMJF7)

• DOT Name: Interferon lambda-2 (IFNL2)
• Synonyms: IFN-lambda-2; Cytokine Zcyto20; Interleukin-28A; IL-28A
• Gene Name: IFNL2
• Related Disease:
  Bladder cancer
  Gastric cancer
  Neoplasm
  Rheumatoid arthritis
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Allergic rhinitis
  Autoimmune disease
  Behcet disease
  Colitis
  Cryohydrocytosis
  Disorder of orbital region
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Lung carcinoma
  Nasal polyp
  Transitional cell carcinoma
  Urothelial carcinoma
  Uveitis
  Zika virus infection
  Chronic obstructive pulmonary disease
  High blood pressure
  Asthma
  Graft-versus-host disease
• UniProt ID: IFNL2_HUMAN
• Pfam ID: PF15177
• Sequence:
  MKLDMTGDCTPVLVLMAAVLTVTGAVPVARLHGALPDARGCHIAQFKSLSPQELQAFKRA
  KDALEESLLLKDCRCHSRLFPRTWDLRQLQVRERPMALEAELALTLKVLEATADTDPALV
  DVLDQPLHTLHHILSQFRACIQPQPTAGPRTRGRLHHWLYRLQEAPKKESPGCLEASVTF
  NLFRLLTRDLNCVASGDLCV
• Function: Cytokine with antiviral, antitumour and immunomodulatory activities. Plays a critical role in the antiviral host defense, predominantly in the epithelial tissues. Acts as a ligand for the heterodimeric class II cytokine receptor composed of IL10RB and IFNLR1, and receptor engagement leads to the activation of the JAK/STAT signaling pathway resulting in the expression of IFN-stimulated genes (ISG), which mediate the antiviral state. Has a restricted receptor distribution and therefore restricted targets: is primarily active in epithelial cells and this cell type-selective action is because of the epithelial cell-specific expression of its receptor IFNLR1. 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. Exerts an immunomodulatory effect by up-regulating MHC class I antigen expression.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway: Interleukin-20 family signaling (R-HSA-8854691)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[4]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[2]
Urinary bladder cancer	DISDV4T7	Definitive	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Definitive	Biomarker	[1]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Biomarker	[6]
Behcet disease	DISSYMBS	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Altered Expression	[8]
Cryohydrocytosis	DISMQHL3	Strong	Altered Expression	[9]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[10]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[5]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[14]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[14]
Uveitis	DISV0RYS	Strong	Biomarker	[10]
Zika virus infection	DISQUCTY	Strong	Biomarker	[15]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[16]
High blood pressure	DISY2OHH	moderate	Biomarker	[16]
Asthma	DISW9QNS	Limited	Biomarker	[17]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[18]

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 Interferon lambda-2 (IFNL2).	[19]

References

• [1] Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A.PLoS One. 2012;7(9):e40267. doi: 10.1371/journal.pone.0040267. Epub 2012 Sep 4.
• [2] Clinical Significance of Serum Type III Interferons in Patients with Gastric Cancer.J Interferon Cytokine Res. 2019 Mar;39(3):155-163. doi: 10.1089/jir.2018.0119. Epub 2019 Jan 23.
• [3] Role of the p38 MAPK signaling pathway in mediating interleukin-28A-induced migration of UMUC-3 cells.Int J Mol Med. 2012 Oct;30(4):945-52. doi: 10.3892/ijmm.2012.1064. Epub 2012 Jul 16.
• [4] Type-III interferons and rheumatoid arthritis: Correlation between interferon lambda 1 (interleukin 29) and antimutated citrullinated vimentin antibody levels.Autoimmunity. 2017 Mar;50(2):82-85. doi: 10.1080/08916934.2017.1289181. Epub 2017 Feb 14.
• [5] Effect of IFN-2 on combined allergic rhinitis with nasal polyps.Eur Rev Med Pharmacol Sci. 2018 Mar;22(6):1588-1594. doi: 10.26355/eurrev_201803_14563.
• [6] 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.
• [7] Interleukin-28A promotes IFN- production by peripheral blood mononuclear cells from patients with Behet's disease.Cell Immunol. 2014 Jul;290(1):116-9. doi: 10.1016/j.cellimm.2014.06.003. Epub 2014 Jun 18.
• [8] 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.
• [9] Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype-genotype correlation study.Genes Immun. 2015 Jul-Aug;16(5):321-9. doi: 10.1038/gene.2015.11. Epub 2015 May 28.
• [10] Interleukin-28A enhances autoimmune disease in a retinal autoimmunity model.Cytokine. 2014 Dec;70(2):179-84. doi: 10.1016/j.cyto.2014.07.252. Epub 2014 Aug 17.
• [11] Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection.Front Immunol. 2019 Feb 4;10:112. doi: 10.3389/fimmu.2019.00112. eCollection 2019.
• [12] Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons.Gastroenterology. 2017 Aug;153(2):566-578.e5. doi: 10.1053/j.gastro.2017.04.021. Epub 2017 Apr 26.
• [13] Mesenchymal stem cells are efficiently transduced with adenoviruses bearing type 35-derived fibers and the transduced cells with the IL-28A gene produces cytotoxicity to lung carcinoma cells co-cultured.BMC Cancer. 2014 Sep 25;14:713. doi: 10.1186/1471-2407-14-713.
• [14] Interleukin-28A triggers wound healing migration of bladder cancer cells via NF-B-mediated MMP-9 expression inducing the MAPK pathway.Cell Signal. 2012 Sep;24(9):1734-42. doi: 10.1016/j.cellsig.2012.04.013. Epub 2012 Apr 25.
• [15] Chromosome 19 microRNAs exert antiviral activity independent from type III interferon signaling.Placenta. 2018 Jan;61:33-38. doi: 10.1016/j.placenta.2017.11.004. Epub 2017 Nov 10.
• [16] Serum cytokine profiles in patients with chronic obstructive pulmonary disease associated pulmonary hypertension identified using protein array.Cytokine. 2018 Nov;111:342-349. doi: 10.1016/j.cyto.2018.09.005. Epub 2018 Sep 28.
• [17] Raised interferon-, type 3 interferon and interferon-stimulated genes - evidence of innate immune activation in neutrophilic asthma.Clin Exp Allergy. 2017 Mar;47(3):313-323. doi: 10.1111/cea.12809. Epub 2016 Oct 14.
• [18] Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling.Int J Radiat Oncol Biol Phys. 2019 Mar 15;103(4):970-976. doi: 10.1016/j.ijrobp.2018.11.038. Epub 2018 Nov 29.
• [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.