Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-15 (IL15)
• Synonyms: IL-15
• Gene Name: IL15
• UniProt ID: IL15_HUMAN
• PDB ID: 2XQB; 2Z3Q; 2Z3R; 4GS7
• Pfam ID: PF02372
• Sequence:
  MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI
  EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN
  SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
• Function: Cytokine that plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites by modulating immune cells of both the innate and adaptive immune systems. Stimulates the proliferation of natural killer cells, T-cells and B-cells and promotes the secretion of several cytokines. In monocytes, induces the production of IL8 and monocyte chemotactic protein 1/CCL2, two chemokines that attract neutrophils and monocytes respectively to sites of infection. Unlike most cytokines, which are secreted in soluble form, IL15 is expressed in association with its high affinity IL15RA on the surface of IL15-producing cells and delivers signals to target cells that express IL2RB and IL2RG receptor subunits. Binding to its receptor triggers the phosphorylation of JAK1 and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3/STAT3 and STAT5. In mast cells, induces the rapid tyrosine phosphorylation of STAT6 and thereby controls mast cell survival and release of cytokines such as IL4.
• Tissue Specificity: Most abundant in placenta and skeletal muscle. It is also detected in the heart, lung, liver and kidney. IL15-S21AA is preferentially expressed in tissues such as testis and thymus.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  TNF sig.ling pathway (hsa04668)
  Intesti.l immune network for IgA production (hsa04672)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway: Interleukin-15 signaling (R-HSA-8983432)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Interleukin-15 (IL15).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-15 (IL15).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interleukin-15 (IL15).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interleukin-15 (IL15).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Interleukin-15 (IL15).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Interleukin-15 (IL15).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interleukin-15 (IL15).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-15 (IL15).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Interleukin-15 (IL15).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interleukin-15 (IL15).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Interleukin-15 (IL15).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Interleukin-15 (IL15).	[12]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Interleukin-15 (IL15).	[14]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Interleukin-15 (IL15).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Interleukin-15 (IL15).	[16]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Interleukin-15 (IL15).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-15 (IL15).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Interleukin-15 (IL15).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interleukin-15 (IL15).	[1]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-15 (IL15).	[10]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Interleukin-15 (IL15).	[21]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Interleukin-15 (IL15).	[22]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Interleukin-15 (IL15).	[23]
Chrysin	DM7V2LG	Investigative	Chrysin decreases the expression of Interleukin-15 (IL15).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the secretion of Interleukin-15 (IL15).	[13]

1 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-15 (IL15).	[18]

References

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• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
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• [8] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [9] Glucocorticoids inhibit cell death in ovarian cancer and up-regulate caspase inhibitor cIAP2. Clin Cancer Res. 2005 Sep 1;11(17):6325-32. doi: 10.1158/1078-0432.CCR-05-0182.
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• [11] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Altered cytokine profiles of human retinal pigment epithelium: oxidant injury and replicative senescence. Mol Vis. 2013;19:718-28. Epub 2013 Mar 21.
• [14] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [15] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [16] Anti-inflammatory effects of dietary phenolic compounds in an in vitro model of inflamed human intestinal epithelium. Chem Biol Interact. 2010 Dec 5;188(3):659-67.
• [17] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
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• [19] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.
• [20] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [21] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [22] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [23] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.