Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYT4LP5)

• DOT Name: Interleukin-36 beta (IL36B)
• Synonyms: FIL1 eta; Interleukin-1 eta; IL-1 eta; Interleukin-1 family member 8; IL-1F8; Interleukin-1 homolog 2; IL-1H2
• Gene Name: IL36B
• Related Disease:
  Non-syndromic ichthyosis
  Psoriasis
  Rheumatoid arthritis
• UniProt ID: IL36B_HUMAN
• Sequence:
  MNPQREAAPKSYAIRDSRQMVWVLSGNSLIAAPLSRSIKPVTLHLIACRDTEFSDKEKGN
  MVYLGIKGKDLCLFCAEIQGKPTLQLKLQGSQDNIGKDTCWKLVGIHTCINLDVRESCFM
  GTLDQWGIGVGRKKWKSSFQHHHLRKKDKDFSSMRTNIGMPGRM
• 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. Stimulates production of interleukin-6 and interleukin-8 in synovial fibrobasts, articular chondrocytes and mature adipocytes. Induces expression of a number of antimicrobial peptides including beta-defensins 4 and 103 as well as a number of matrix metalloproteases. 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.
• Tissue Specificity: Expression at low levels in tonsil, bone marrow, heart, placenta, lung, testis and colon but not in any hematopoietic cell lines. Not detected in adipose tissue. Expressed at higher levels in psoriatic plaques than in symptomless psoriatic skin or healthy control skin. Increased levels are not detected in inflamed joint tissue.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Interleukin-36 pathway (R-HSA-9014826)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Biomarker	[1]
Psoriasis	DIS59VMN	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Interleukin-36 beta (IL36B).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Interleukin-36 beta (IL36B).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Interleukin-36 beta (IL36B).	[5]

References

• [1] Ichthyosis molecular fingerprinting shows profound T(H)17 skewing and a unique barrier genomic signature.J Allergy Clin Immunol. 2019 Feb;143(2):604-618. doi: 10.1016/j.jaci.2018.03.021. Epub 2018 May 24.
• [2] The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes.Arthritis Res Ther. 2006;8(3):R80. doi: 10.1186/ar1946. Epub 2006 Apr 28.
• [3] 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.
• [4] 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.
• [5] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.