Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JF8A3)

• DOT Name: Interleukin-12 subunit beta (IL12B)
• Synonyms: IL-12B; Cytotoxic lymphocyte maturation factor 40 kDa subunit; CLMF p40; IL-12 subunit p40; NK cell stimulatory factor chain 2; NKSF2
• Gene Name: IL12B
• Related Disease: Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
• UniProt ID: IL12B_HUMAN
• PDB ID: 1F42; 1F45; 3D85; 3D87; 3DUH; 3HMX; 3QWR; 4GRW; 5MJ3; 5MJ4; 5MXA; 5MZV; 5NJD; 6UIB; 6WDQ
• Pfam ID: PF10420
• Sequence:
  MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITW
  TLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ
  KEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV
  RGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKN
  LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC
  RKNASISVRAQDRYYSSSWSEWASVPCS
• Function: Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC; Associates with IL23A to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of pro-inflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Toll-like receptor sig.ling pathway (hsa04620)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Alcoholic liver disease (hsa04936)
  Type I diabetes mellitus (hsa04940)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Inflammatory bowel disease (hsa05321)
  Allograft rejection (hsa05330)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Interleukin-12 signaling (R-HSA-9020591)
  Interleukin-23 signaling (R-HSA-9020933)
  Interleukin-10 signaling (R-HSA-6783783)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency	DISKKRBM	Definitive	Autosomal recessive	[1]

20 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-12 subunit beta (IL12B).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interleukin-12 subunit beta (IL12B).	[3]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Interleukin-12 subunit beta (IL12B).	[4]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Interleukin-12 subunit beta (IL12B).	[5]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Interleukin-12 subunit beta (IL12B).	[6]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Interleukin-12 subunit beta (IL12B).	[7]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide decreases the expression of Interleukin-12 subunit beta (IL12B).	[8]
Ergotidine	DM78IME	Approved	Ergotidine decreases the expression of Interleukin-12 subunit beta (IL12B).	[10]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Interleukin-12 subunit beta (IL12B).	[11]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate decreases the expression of Interleukin-12 subunit beta (IL12B).	[12]
Bryostatin-1	DM1JOXY	Phase 2	Bryostatin-1 decreases the expression of Interleukin-12 subunit beta (IL12B).	[11]
Resiquimod	DML6XSP	Phase 2	Resiquimod increases the expression of Interleukin-12 subunit beta (IL12B).	[13]
RGI-2001	DM4AC2F	Phase 2	RGI-2001 increases the expression of Interleukin-12 subunit beta (IL12B).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Interleukin-12 subunit beta (IL12B).	[16]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Interleukin-12 subunit beta (IL12B).	[17]
Nitrosoglutathione	DMZ9WI4	Investigative	Nitrosoglutathione decreases the expression of Interleukin-12 subunit beta (IL12B).	[8]
CYANATE	DM6HQDL	Investigative	CYANATE increases the expression of Interleukin-12 subunit beta (IL12B).	[22]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the expression of Interleukin-12 subunit beta (IL12B).	[23]
Suramin	DMTOUY9	Investigative	Suramin increases the expression of Interleukin-12 subunit beta (IL12B).	[24]
amthamine	DMBAX3P	Investigative	amthamine decreases the expression of Interleukin-12 subunit beta (IL12B).	[10]

5 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-12 subunit beta (IL12B).	[9]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the secretion of Interleukin-12 subunit beta (IL12B).	[18]
Beta-D-Glucose	DM5IHYP	Investigative	Beta-D-Glucose increases the secretion of Interleukin-12 subunit beta (IL12B).	[19]
Serotonin	DMOFCRY	Investigative	Serotonin affects the secretion of Interleukin-12 subunit beta (IL12B).	[20]
muramyl dipeptide	DM4FR71	Investigative	muramyl dipeptide increases the secretion of Interleukin-12 subunit beta (IL12B).	[21]

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 affects the methylation of Interleukin-12 subunit beta (IL12B).	[15]

References

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• [2] Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015 Apr;35(4):398-406. doi: 10.1002/jat.3033. Epub 2014 Aug 4.
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• [5] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
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• [7] Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood. 2001 Jun 1;97(11):3466-9. doi: 10.1182/blood.v97.11.3466.
• [8] Regulatory role of nitric oxide on monocyte-derived dendritic cell functions. J Interferon Cytokine Res. 2003 Aug;23(8):423-31. doi: 10.1089/107999003322277838.
• [9] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [10] Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. J Clin Invest. 1998 Nov 15;102(10):1866-73. doi: 10.1172/JCI3692.
• [11] Effect of serum and antioxidants on the immunogenicity of protein kinase C-activated chronic lymphocytic leukemia cells. J Immunother. 2005 Jan-Feb;28(1):28-39. doi: 10.1097/00002371-200501000-00004.
• [12] 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.
• [13] Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells. J Exp Med. 2008 Jun 9;205(6):1447-61. doi: 10.1084/jem.20071450. Epub 2008 May 19.
• [14] Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med. 2005 May 2;201(9):1503-17. doi: 10.1084/jem.20042592.
• [15] 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.
• [16] Interleukin-12 was not involved in promotion of T helper cell differentiation induced by theophylline. Acta Pharmacol Sin. 2004 Dec;25(12):1666-70.
• [17] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [18] Mechanistic understanding of dendritic cell activation in skin sensitization: additional evidences to support potency classification. Toxicol Lett. 2020 Apr 1;322:50-57. doi: 10.1016/j.toxlet.2020.01.014. Epub 2020 Jan 17.
• [19] Proinflammatory response of immature human dendritic cells is mediated by dectin-1 after exposure to Aspergillus fumigatus germ tubes. J Infect Dis. 2008 Mar 15;197(6):924-31. doi: 10.1086/528694.
• [20] 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol. 2005 May;17(5):599-606. doi: 10.1093/intimm/dxh242. Epub 2005 Mar 31.
• [21] Dendritic cell maturation induced by muramyl dipeptide (MDP) derivatives: monoacylated MDP confers TLR2/TLR4 activation. J Immunol. 2005 Jun 1;174(11):7096-103. doi: 10.4049/jimmunol.174.11.7096.
• [22] Isocyanates induces DNA damage, apoptosis, oxidative stress, and inflammation in cultured human lymphocytes. J Biochem Mol Toxicol. 2008 Nov-Dec;22(6):429-40.
• [23] Expression and regulation of interleukin-23 subunits in human peripheral blood mononuclear cells and hematopoietic cell lines in response to various inducers. Cell Biol Int. 2004;28(10):689-97. doi: 10.1016/j.cellbi.2004.07.002.
• [24] Biological inactivation and impaired detection of IL-10 by suramin. J Immunol Methods. 2005 Apr;299(1-2):91-8. doi: 10.1016/j.jim.2005.01.008. Epub 2005 Feb 17.