Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHBEL5H)

• DOT Name: Interleukin-36 alpha (IL36A)
• Synonyms: FIL1 epsilon; Interleukin-1 epsilon; IL-1 epsilon; Interleukin-1 family member 6; IL-1F6
• Gene Name: IL36A
• Related Disease:
  Advanced cancer
  Epithelial ovarian cancer
  Graves disease
  Immune system disorder
  Inflammatory bowel disease
  Neuromyelitis optica
  Postmenopausal osteoporosis
  Chronic pancreatitis
• UniProt ID: IL36A_HUMAN
• PDB ID: 6HPI
• Pfam ID: PF00340
• Sequence:
  MEKALKIDTPQQGSIQDINHRVWVLQDQTLIAVPRKDRMSPVTIALISCRHVETLEKDRG
  NPIYLGLNGLNLCLMCAKVGDQPTLQLKEKDIMDLYNQPEPVKSFLFYHSQSGRNSTFES
  VAFPGWFIAVSSEGGCPLILTQELGKANTTDFGLTMLF
• Function: Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells linked to a pro-inflammatory response. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1, and the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. In cultured monocytes up-regulates expression of IL-1A, IL-1B and IL-6. In myeloid dendritic cells involved in cell maturation by up-regulating surface expression of CD83, CD86 and HLA-DR. In monocyte-derived dendritic cells facilitates dendritic cell maturation and drives T-cell proliferation. May play a role in pro-inflammatory effects in the lung.
• Tissue Specificity: Expressed in immune system and fetal brain, but not in other tissues tested or in multiple hematopoietic cell lines. Predominantly expressed in skin keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Increased in lesional psoriasis skin.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Interleukin-36 pathway (R-HSA-9014826)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Graves disease	DISU4KOQ	Strong	Biomarker	[2]
Immune system disorder	DISAEGPH	Strong	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[3]
Neuromyelitis optica	DISBFGKL	Strong	Altered Expression	[4]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Genetic Variation	[5]
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[6]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Interleukin-36 alpha (IL36A).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interleukin-36 alpha (IL36A).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-36 alpha (IL36A).	[8]

References

• [1] IL-36 suppresses proliferation of ovarian cancer cells.Tumour Biol. 2017 Jun;39(6):1010428317706918. doi: 10.1177/1010428317706918.
• [2] Elevated Interleukin-36 And CD4(+)IL-36(+)T Cells Are Involved in the Pathogenesis of Graves' Disease.Front Endocrinol (Lausanne). 2018 Oct 9;9:591. doi: 10.3389/fendo.2018.00591. eCollection 2018.
• [3] Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation.Gastroenterology. 2019 Mar;156(4):1082-1097.e11. doi: 10.1053/j.gastro.2018.11.029. Epub 2018 Nov 16.
• [4] Interleukin-36 alpha levels are elevated in the serum and cerebrospinal fluid of patients with neuromyelitis optica spectrum disorder and correlate with disease activity.Immunobiology. 2019 May;224(3):397-401. doi: 10.1016/j.imbio.2019.02.008. Epub 2019 Mar 1.
• [5] Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study.Bone. 2002 Jul;31(1):43-50. doi: 10.1016/s8756-3282(02)00810-4.
• [6] Interleukin-36 Induces Inflammatory Mediators From Human Pancreatic Myofibroblasts Via a MyD88 Dependent Pathway.Pancreas. 2017 Apr;46(4):539-548. doi: 10.1097/MPA.0000000000000765.
• [7] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [8] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.