Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19IAAS)

• DOT Name: Interleukin-36 gamma (IL36G)
• Synonyms: IL-1-related protein 2; IL-1RP2; Interleukin-1 epsilon; IL-1 epsilon; Interleukin-1 family member 9; IL-1F9; Interleukin-1 homolog 1; IL-1H1
• Gene Name: IL36G
• UniProt ID: IL36G_HUMAN
• PDB ID: 4IZE; 4P0J; 4P0K; 4P0L; 6P9E
• Pfam ID: PF00340
• Sequence:
  MRGTPGDADGGGRAVYQSMCKPITGTINDLNQQVWTLQGQNLVAVPRSDSVTPVTVAVIT
  CKYPEALEQGRGDPIYLGIQNPEMCLYCEKVGEQPTLQLKEQKIMDLYGQPEPVKPFLFY
  RAKTGRTSTLESVAFPDWFIASSKRDQPIILTSELGKSYNTAFELNIND
• 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. 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; also stimulates its own expression and that of the prototypic cutaneous pro-inflammatory parameters TNF-alpha, S100A7/psoriasin and inducible NOS. May play a role in pro-inflammatory responses during particular neutrophilic airway inflammation: activates mitogen-activated protein kinases and NF-kappa B in primary lung fibroblasts, and stimulates the expression of IL-8 and CXCL3 and Th17 chemokine CCL20 in lung fibroblasts. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus.
• Tissue Specificity: Highly expressed in tissues containing epithelial cells: skin, lung, stomach and esophagus. Expressed in bronchial epithelial. In skin is expressed only in keratinocytes but not in fibroblasts, endothelial cells or melanocytes. Up-regulated in lesional psoriasis skin. Expressed in monocyte-derived dendritic cells and M1 macrophages.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Interleukin-36 pathway (R-HSA-9014826)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Interleukin-36 gamma (IL36G).	[1]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interleukin-36 gamma (IL36G).	[2]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Interleukin-36 gamma (IL36G).	[3]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Interleukin-36 gamma (IL36G).	[4]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Interleukin-36 gamma (IL36G).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-36 gamma (IL36G).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interleukin-36 gamma (IL36G).	[2]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Interleukin-36 gamma (IL36G).	[7]

References

• [1] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [2] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [3] 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.
• [4] 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.
• [5] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [6] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.