Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTABCY4W)

• DOT Name: Interleukin-21 (IL21)
• Synonyms: IL-21; Za11
• Gene Name: IL21
• Related Disease:
  IL21-related infantile inflammatory bowel disease
  Common variable immunodeficiency
• UniProt ID: IL21_HUMAN
• PDB ID: 2OQP; 3TGX; 8ENT
• Pfam ID: PF02372
• Sequence:
  MRSSPGNMERIVICLMVIFLGTLVHKSSSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEF
  LPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRL
  TCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS
• Function: Cytokine with immunoregulatory activity. May promote the transition between innate and adaptive immunity. Induces the production of IgG(1) and IgG(3) in B-cells. Implicated in the generation and maintenance of T follicular helper (Tfh) cells and the formation of germinal-centers. Together with IL6, control the early generation of Tfh cells and are critical for an effective antibody response to acute viral infection. May play a role in proliferation and maturation of natural killer (NK) cells in synergy with IL15. May regulate proliferation of mature B- and T-cells in response to activating stimuli. In synergy with IL15 and IL18 stimulates interferon gamma production in T-cells and NK cells. During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation.
• Tissue Specificity: Expressed in activated CD4-positive T-cells but not in CD8-positive T-cells, B-cells, or monocytes.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  Th17 cell differentiation (hsa04659)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway: Interleukin-21 signaling (R-HSA-9020958)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
IL21-related infantile inflammatory bowel disease	DISL5J5L	Supportive	Autosomal recessive	[1]
Common variable immunodeficiency	DISHE7JQ	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Interleukin-21 (IL21).	[3]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Interleukin-21 (IL21).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Interleukin-21 (IL21).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-21 (IL21).	[6]
SGC-CBP30	DMTLRGZ	Investigative	SGC-CBP30 decreases the expression of Interleukin-21 (IL21).	[7]

References

• [1] Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009 Nov 19;361(21):2033-45. doi: 10.1056/NEJMoa0907206. Epub 2009 Nov 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [4] 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.
• [5] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [6] 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.
• [7] 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.