Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT5YWK3)

• DOT Name: Interleukin-33 (IL33)
• Synonyms: IL-33; Interleukin-1 family member 11; IL-1F11; Nuclear factor from high endothelial venules; NF-HEV
• Gene Name: IL33
• UniProt ID: IL33_HUMAN
• PDB ID: 2KLL; 4KC3
• Pfam ID: PF15095
• Sequence:
  MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSGLMIKKEACYF
  RRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGVQKYTRALHDSSITGISPIT
  EYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHPSNESGDGVDGK
  MLMVTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFI
  GVKDNHLALIKVDSSENLCTENILFKLSET
• Function: Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as an enhancer of polarization of alternatively activated macrophages. Acts as a chemoattractant for Th2 cells, and may function as an 'alarmin', that amplifies immune responses during tissue injury. Induces rapid UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages; In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or pro-inflammatory activation.
• Tissue Specificity: Expressed at high level in high endothelial venules found in tonsils, Peyer patches and mesenteric lymph nodes. Almost undetectable in placenta.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Necroptosis (hsa04217)
  Cytosolic D.-sensing pathway (hsa04623)
  Influenza A (hsa05164)
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Interleukin-33 signaling (R-HSA-9014843)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Interleukin-33 (IL33).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interleukin-33 (IL33).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-33 (IL33).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Interleukin-33 (IL33).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Interleukin-33 (IL33).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Interleukin-33 (IL33).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Interleukin-33 (IL33).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Interleukin-33 (IL33).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Interleukin-33 (IL33).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Interleukin-33 (IL33).	[11]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Interleukin-33 (IL33).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interleukin-33 (IL33).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Interleukin-33 (IL33).	[14]
Staurosporine	DM0E9BR	Investigative	Staurosporine increases the expression of Interleukin-33 (IL33).	[15]
Lysophosphatidylcholine	DMOGFVH	Investigative	Lysophosphatidylcholine increases the expression of Interleukin-33 (IL33).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Nicotine	DMWX5CO	Approved	Nicotine increases the secretion of Interleukin-33 (IL33).	[10]

References

• [1] 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.
• [2] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] Triclosan Induces Thymic Stromal Lymphopoietin in Skin Promoting Th2 Allergic Responses. Toxicol Sci. 2015 Sep;147(1):127-39. doi: 10.1093/toxsci/kfv113. Epub 2015 Jun 5.
• [6] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [7] The effects of bisphenol A and bisphenol S on adipokine expression and glucose metabolism in human adipose tissue. Toxicology. 2020 Dec 1;445:152600. doi: 10.1016/j.tox.2020.152600. Epub 2020 Sep 22.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] The PPAR-dependent effect of flavonoid luteolin against damage induced by the chemotherapeutic irinotecan in human intestinal cells. Chem Biol Interact. 2022 Jan 5;351:109712. doi: 10.1016/j.cbi.2021.109712. Epub 2021 Oct 23.
• [10] Cigarette smoke extract interferes with placenta macrophage functions: A new mechanism to compromise placenta functions?. Reprod Toxicol. 2018 Jun;78:120-129. doi: 10.1016/j.reprotox.2018.04.009. Epub 2018 Apr 16.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] Inhibition of thymic stromal lymphopoietin production by FK3453. J Pharmacol Sci. 2022 Aug;149(4):198-204. doi: 10.1016/j.jphs.2022.05.005. Epub 2022 May 21.
• [13] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver. J Mol Med (Berl). 2015 Aug;93(8):867-78. doi: 10.1007/s00109-015-1270-6. Epub 2015 Mar 8.
• [16] Lysophosphatidylcholine induces apoptosis and inflammatory damage in brain microvascular endothelial cells via GPR4-mediated NLRP3 inflammasome activation. Toxicol In Vitro. 2021 Dec;77:105227. doi: 10.1016/j.tiv.2021.105227. Epub 2021 Jul 20.