Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4H8YRL)

• DOT Name: Interleukin-37 (IL37)
• Synonyms: IL-37; FIL1 zeta; IL-1X; Interleukin-1 family member 7; IL-1F7; Interleukin-1 homolog 4; IL-1H; IL-1H4; Interleukin-1 zeta; IL-1 zeta; Interleukin-1-related protein; IL-1RP1
• Gene Name: IL37
• Related Disease: Inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive
• UniProt ID: IL37_HUMAN
• PDB ID: 5HN1; 6NCU
• Pfam ID: PF00340
• Sequence:
  MSFVGENSGVKMGSEDWEKDEPQCCLEDPAGSPLEPGPSLPTMNFVHTSPKVKNLNPKKF
  SIHDQDHKVLVLDSGNLIAVPDKNYIRPEIFFALASSLSSASAEKGSPILLGVSKGEFCL
  YCDKDKGQSHPSLQLKKEKLMKLAAQKESARRPFIFYRAQVGSWNMLESAAHPGWFICTS
  CNCNEPVGVTDKFENRKHIEFSFQPVCKAEMSPSEVSD
• Function: Immune regulatory cytokine that acts as a suppressor of innate inflammatory and immune responses involved in curbing excessive inflammation. Signaling can occur via two mechanisms, intracellularly through nuclear translocation with SMAD3 and extracellularly after secretion and binding to its receptor composed of IL18R1 and IL18RAP. Suppresses, or reduces, pro-inflammatory cytokine production, including IL1A and IL6, as well as CCL12, CSF1, CSF2, CXCL13, IL1B, IL23A and IL1RN, but spares anti-inflammatory cytokines. Inhibits dendritic cell activation.
• Tissue Specificity: In general, low constitutive expression, if any, in healthy tissues; high expression in inflammatory counterparts, including in synovial tissues from individuals with active rheumatoid arthritis. Isoform A, isoform B and isoform C are expressed in testis, colon, placenta, lung and lymph node. Isoform D and isoform E were found only in testis and bone marrow. Whereas only isoform A is found in brain, only isoform B in kidney and only isoform C in heart.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
• Reactome Pathway:
  Interleukin-18 signaling (R-HSA-9012546)
  Interleukin-37 signaling (R-HSA-9008059)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive	DISQRTAF	Limited	Unknown	[1]

2 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-37 (IL37).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interleukin-37 (IL37).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interleukin-37 (IL37).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interleukin-37 (IL37).	[4]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Interleukin-37 (IL37).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Interleukin-37 (IL37).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Interleukin-37 (IL37).	[8]

References

• [1] Genomic Variant in IL-37 Confers A Significant Risk of Coronary Artery Disease. Sci Rep. 2017 Feb 9;7:42175. doi: 10.1038/srep42175.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [6] 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.
• [7] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.