Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY72FT2)

• DOT Name: Interleukin-17A (IL17A)
• Synonyms: IL-17; IL-17A; Cytotoxic T-lymphocyte-associated antigen 8; CTLA-8
• Gene Name: IL17A
• UniProt ID: IL17_HUMAN
• PDB ID: 2VXS; 4HR9; 4HSA; 4QHU; 5HHV; 5HHX; 5HI3; 5HI4; 5HI5; 5N7W; 5N92; 5NAN; 5VB9; 6WIO; 6WIR; 7AMA; 7AMG; 7UWM; 7UWN; 7WKX; 7Z2M; 7ZAN; 8B7W; 8CDG; 8DY1; 8DY5; 8DYF; 8DYG; 8DYH; 8DYI
• Pfam ID: PF06083
• Sequence:
  MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNP
  KRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCINADGNVDYHMNSVPIQQEIL
  VLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVA
• Function: Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation. Plays an important role in connecting T cell-mediated adaptive immunity and acute inflammatory response to destroy extracellular bacteria and fungi. As a signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites. In airway epithelium, mediates neutrophil chemotaxis via induction of CXCL1 and CXCL5 chemokines. In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells. Effector cytokine of a subset of gamma-delta T cells that functions as part of an inflammatory circuit downstream IL1B, TLR2 and IL23A-IL12B to promote neutrophil recruitment for efficient bacterial clearance. Effector cytokine of innate immune cells including invariant natural killer cell (iNKT) and group 3 innate lymphoid cells that mediate initial neutrophilic inflammation. Involved in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection. Upon acute injury, has a direct role in epithelial barrier formation by regulating OCLN localization and tight junction biogenesis. As part of the mucosal immune response induced by commensal bacteria, enhances host's ability to resist pathogenic bacterial and fungal infections by promoting neutrophil recruitment and antimicrobial peptides release. In synergy with IL17F, mediates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers. Involved in antiviral host defense through various mechanisms. Enhances immunity against West Nile virus by promoting T cell cytotoxicity. May play a beneficial role in influenza A virus (H5N1) infection by enhancing B cell recruitment and immune response in the lung. Contributes to influenza A virus (H1N1) clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense.
• Tissue Specificity: Expressed in memory Th17 cells (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  IL-17 sig.ling pathway (hsa04657)
  Th17 cell differentiation (hsa04659)
  Alcoholic liver disease (hsa04936)
  Inflammatory bowel disease (hsa05321)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Interleukin-17 signaling (R-HSA-448424)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Interleukin-17A (IL17A) affects the response to substance of Aspirin.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Interleukin-17A (IL17A).	[1]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interleukin-17A (IL17A).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Interleukin-17A (IL17A).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-17A (IL17A).	[4]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Interleukin-17A (IL17A).	[5]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Interleukin-17A (IL17A).	[6]
Paroxetine	DM5PVQE	Approved	Paroxetine decreases the expression of Interleukin-17A (IL17A).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Interleukin-17A (IL17A).	[9]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate decreases the expression of Interleukin-17A (IL17A).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-17A (IL17A).	[12]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Interleukin-17A (IL17A).	[14]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Interleukin-17A (IL17A).	[15]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Interleukin-17A (IL17A).	[16]
SGC-CBP30	DMTLRGZ	Investigative	SGC-CBP30 decreases the expression of Interleukin-17A (IL17A).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoniazid	DM5JVS3	Approved	Isoniazid increases the secretion of Interleukin-17A (IL17A).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the secretion of Interleukin-17A (IL17A).	[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-17A (IL17A).	[11]

References

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• [2] [As(2)O(3) Up-Regulates the Proportion of CD4(+)CD25(+)CD127(low) Tregs in Peripheral Blood of Patients with Severe Aplastic Anemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018 Jun;26(3):854-858. doi: 10.7534/j.issn.1009-2137.2018.03.037.
• [3] Regulatory T cell function correlates with serum 25-hydroxyvitamin D, but not with 1,25-dihydroxyvitamin D, parathyroid hormone and calcium levels in patients with relapsing remitting multiple sclerosis. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):243-6. doi: 10.1016/j.jsbmb.2010.03.001. Epub 2010 Mar 6.
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• [5] Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC). Front Microbiol. 2015 Dec 22;6:1452. doi: 10.3389/fmicb.2015.01452. eCollection 2015.
• [6] Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008 May 15;180(10):6988-96. doi: 10.4049/jimmunol.180.10.6988.
• [7] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [8] Paroxetine modulates immune responses by activating a JAK2/STAT3 signaling pathway. J Biochem Mol Toxicol. 2020 May;34(5):e22464. doi: 10.1002/jbt.22464. Epub 2020 Feb 5.
• [9] Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37-48. doi: 10.1007/s10557-012-6427-8.
• [10] New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am J Clin Dermatol. 2011 Apr 1;12(2):113-25. doi: 10.2165/11538950-000000000-00000.
• [11] 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.
• [12] BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J. 2013 Jul 19;3(7):e126. doi: 10.1038/bcj.2013.24.
• [13] Differential influences of the BPA, BPS and BPF on in vitro IL-17 secretion by mouse and human T cells. Toxicol In Vitro. 2020 Dec;69:104993. doi: 10.1016/j.tiv.2020.104993. Epub 2020 Sep 8.
• [14] Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain. Environ Int. 2022 Nov;169:107512. doi: 10.1016/j.envint.2022.107512. Epub 2022 Sep 8.
• [15] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [16] Effects of the organophosphate insecticides phosmet and chlorpyrifos on trophoblast JEG-3 cell death, proliferation and inflammatory molecule production. Toxicol In Vitro. 2012 Apr;26(3):406-13. doi: 10.1016/j.tiv.2012.01.003. Epub 2012 Jan 12.
• [17] CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10768-73. doi: 10.1073/pnas.1501956112. Epub 2015 Aug 10.
• [18] IL-13 and IL-17A gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2011 Dec;107(6):510-6. doi: 10.1016/j.anai.2011.09.003. Epub 2011 Sep 22.