Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTII0RM0)

DOT Name	Tumor necrosis factor alpha-induced protein 8-like protein 2 (TNFAIP8L2)
Synonyms	TIPE2; TNF alpha-induced protein 8-like protein 2; TNFAIP8-like protein 2; Inflammation factor protein 20
Gene Name	TNFAIP8L2
Related Disease	Liver cirrhosis ( ) Parkinson disease ( ) Primary biliary cholangitis ( ) Prostate cancer ( ) Prostate carcinoma ( ) Thyroid gland papillary carcinoma ( ) Advanced cancer ( ) Alzheimer disease ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Autoimmune disease ( ) Cardiovascular disease ( ) Chronic hepatitis B virus infection ( ) Cognitive impairment ( ) Colon cancer ( ) Colon carcinoma ( ) Glioma ( ) Hepatitis ( ) Hepatitis A virus infection ( ) Hepatitis C virus infection ( ) Hepatocellular carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Neoplasm ( ) Osteoporosis ( ) Pneumonia ( ) Pneumonitis ( ) Psoriasis ( ) Psoriatic arthritis ( ) Systemic lupus erythematosus ( ) Carcinoma ( ) Carcinoma of esophagus ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Gastrointestinal stromal tumour ( ) Hepatitis B virus infection ( ) Liver cancer ( ) Rheumatoid arthritis ( ) Ankylosing spondylitis ( ) Asthma ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Neuroblastoma ( ) Non-insulin dependent diabetes ( ) Osteosarcoma ( ) Stroke ( )
UniProt ID	TP8L2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3F4M
Pfam ID	PF05527
Sequence	MESFSSKSLALQAEKKLLSKMAGRSVAHLFIDETSSEVLDELYRVSKEYTHSRPQAQRVI KDLIKVAIKVAVLHRNGSFGPSELALATRFRQKLRQGAMTALSFGEVDFTFEAAVLAGLL TECRDVLLELVEHHLTPKSHGRIRHVFDHFSDPGLLTALYGPDFTQHLGKICDGLRKLLD EGKL
Function	Acts as a negative regulator of innate and adaptive immunity by maintaining immune homeostasis. Plays a regulatory role in the Toll-like signaling pathway by determining the strength of LPS-induced signaling and gene expression. Inhibits TCR-mediated T-cell activation and negatively regulate T-cell function to prevent hyperresponsiveness. Inhibits also autolysosome formation via negatively modulating MTOR activation by interacting with RAC1 and promoting the disassociation of the RAC1-MTOR complex. Plays an essential role in NK-cell biology by acting as a checkpoint and displaying an expression pattern correlating with NK-cell maturation process and by negatively regulating NK-cell maturation and antitumor immunity. Mechanistically, suppresses IL-15-triggered mTOR activity in NK-cells.
Tissue Specificity	Expressed in T-cells, B-cells, macrophages, neurons in the brain and brainstem, and stratified squamous epithelia of the esophagus, cervix and skin.
Reactome Pathway	PI Metabolism (R-HSA-1483255 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Liver cirrhosis	DIS4G1GX	Definitive	Altered Expression	[1]
Parkinson disease	DISQVHKL	Definitive	Altered Expression	[2]
Primary biliary cholangitis	DIS43E0O	Definitive	Altered Expression	[3]
Prostate cancer	DISF190Y	Definitive	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[7]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[8]
Autoimmune disease	DISORMTM	Strong	Biomarker	[9]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[10]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Biomarker	[11]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[12]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Hepatitis	DISXXX35	Strong	Altered Expression	[14]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[14]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Osteoporosis	DISF2JE0	Strong	Biomarker	[17]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[18]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[18]
Psoriasis	DIS59VMN	Strong	Biomarker	[9]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[19]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[20]
Carcinoma	DISH9F1N	moderate	Biomarker	[21]
Carcinoma of esophagus	DISS6G4D	moderate	Biomarker	[21]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[22]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[23]
Hepatitis B virus infection	DISLQ2XY	moderate	Altered Expression	[1]
Liver cancer	DISDE4BI	moderate	Altered Expression	[22]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[24]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[25]
Asthma	DISW9QNS	Limited	Biomarker	[26]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[27]
Breast cancer	DIS7DPX1	Limited	Biomarker	[28]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[28]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[29]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[30]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[27]
Stroke	DISX6UHX	Limited	Altered Expression	[31]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor necrosis factor alpha-induced protein 8-like protein 2 (TNFAIP8L2).	[32]
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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 decreases the methylation of Tumor necrosis factor alpha-induced protein 8-like protein 2 (TNFAIP8L2).	[33]
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References

1	Tumor necrosis factor--induced protein 8-like 2 mRNA in peripheral blood mononuclear cells is associated with the disease progression of chronic hepatitis B virus infection.Virol J. 2019 Oct 28;16(1):120. doi: 10.1186/s12985-019-1224-7.
2	Correlation of serum levels and gene expression of tumor necrosis factor--induced protein-8 like-2 with Parkinson disease severity.Metab Brain Dis. 2018 Dec;33(6):1955-1959. doi: 10.1007/s11011-018-0302-7. Epub 2018 Aug 13.
3	Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis.J Gastroenterol Hepatol. 2016 Jun;31(6):1177-83. doi: 10.1111/jgh.13251.
4	TIPE2 Overexpression Suppresses the Proliferation, Migration, and Invasion in Prostate Cancer Cells by Inhibiting PI3K/Akt Signaling Pathway.Oncol Res. 2016;24(5):305-313. doi: 10.3727/096504016X14666990347437.
5	TIPE2 acts as a biomarker for tumor aggressiveness and suppresses cell invasiveness in papillary thyroid cancer (PTC).Cell Biosci. 2018 Aug 31;8:49. doi: 10.1186/s13578-018-0247-x. eCollection 2018.
6	Tumour necrosis factor--induced protein 8-like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells.J Cell Mol Med. 2019 Mar;23(3):1698-1713. doi: 10.1111/jcmm.14065. Epub 2019 Jan 13.
7	Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice.J Neuroimmune Pharmacol. 2019 Sep;14(3):519-529. doi: 10.1007/s11481-019-09861-2. Epub 2019 Jul 8.
8	TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway.Exp Ther Med. 2019 Apr;17(4):2937-2944. doi: 10.3892/etm.2019.7316. Epub 2019 Feb 26.
9	Loss of TIPE2 Has Opposing Effects on the Pathogenesis of Autoimmune Diseases.Front Immunol. 2019 Sep 24;10:2284. doi: 10.3389/fimmu.2019.02284. eCollection 2019.
10	Genome-wide analysis reveals TNFAIP8L2 as an immune checkpoint regulator of inflammation and metabolism.Mol Immunol. 2018 Jul;99:154-162. doi: 10.1016/j.molimm.2018.05.007. Epub 2018 May 19.
11	TIPE2 as a potential therapeutic target in chronic viral hepatitis.Expert Opin Ther Targets. 2019 Jun;23(6):485-493. doi: 10.1080/14728222.2019.1608948. Epub 2019 Apr 22.
12	A novel inflammatory regulator TIPE2 inhibits TLR4-mediated development of colon cancer via caspase-8.Cancer Biomark. 2014;14(4):233-40. doi: 10.3233/CBM-140402.
13	TIPE2 Inhibits Hypoxia-Induced Wnt/-Catenin Pathway Activation and EMT in Glioma Cells.Oncol Res. 2016;24(4):255-61. doi: 10.3727/096504016X14666990347356.
14	Tumor necrosis factor--induced protein 8-like 2 (TIPE2) is associated with immune phases of patients with chronic hepatitis B.Oncotarget. 2017 May 9;8(19):30781-30792. doi: 10.18632/oncotarget.15683.
15	TIPE2 Induced the Proliferation, Survival, and Migration of Lung Cancer Cells Through Modulation of Akt/mTOR/NF-B Signaling Cascade.Biomolecules. 2019 Dec 6;9(12):836. doi: 10.3390/biom9120836.
16	TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis.J Exp Med. 2020 Feb 3;217(2):e20182005. doi: 10.1084/jem.20182005.
17	Reduced TIPE2 expression is inversely associated with proinflammatory cytokines and positively correlated with bone mineral density in patients with osteoporosis.Life Sci. 2019 Jan 1;216:227-232. doi: 10.1016/j.lfs.2018.11.054. Epub 2018 Nov 27.
18	TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury.Inflamm Res. 2019 Nov;68(11):981-992. doi: 10.1007/s00011-019-01280-6. Epub 2019 Sep 5.
19	TIPE2 Suppresses Pseudomonas aeruginosa Keratitis by Inhibiting NF-B Signaling and the Infiltration of Inflammatory Cells.J Infect Dis. 2019 Aug 9;220(6):1008-1018. doi: 10.1093/infdis/jiz246.
20	Down-regulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.Clin Immunol. 2009 Dec;133(3):422-7. doi: 10.1016/j.clim.2009.08.014. Epub 2009 Sep 12.
21	TIPE2 suppresses progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/-catenin pathway.J Transl Med. 2018 Jan 17;16(1):7. doi: 10.1186/s12967-018-1383-0.
22	The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras.Mol Cell. 2012 Mar 9;45(5):610-8. doi: 10.1016/j.molcel.2012.01.006. Epub 2012 Feb 8.
23	TIPE2 acts as a biomarker for GIST risk category and suppresses the viability and invasiveness of GIST cells.Cell Biosci. 2018 Dec 5;8:62. doi: 10.1186/s13578-018-0261-z. eCollection 2018.
24	TIPE2 expression is increased in peripheral blood mononuclear cells from patients with rheumatoid arthritis.Oncotarget. 2017 Sep 23;8(50):87472-87479. doi: 10.18632/oncotarget.21267. eCollection 2017 Oct 20.
25	Increased expression of TIPE2 mRNA in PBMCs of patients with ankylosing spondylitis is negatively associated with the disease severity.Hum Immunol. 2017 Feb;78(2):232-237. doi: 10.1016/j.humimm.2016.11.001. Epub 2016 Nov 2.
26	TIPE2 is negatively correlated with tissue factor and thrombospondin-1 expression in patients with bronchial asthma.Exp Ther Med. 2018 Apr;15(4):3449-3454. doi: 10.3892/etm.2018.5870. Epub 2018 Feb 14.
27	TIPE2 sensitizes osteosarcoma cells to cis-platin by down-regulating MDR1 via the TAK1- NF-B and - AP-1 pathways.Mol Immunol. 2018 Sep;101:471-478. doi: 10.1016/j.molimm.2018.08.010. Epub 2018 Aug 14.
28	Gene delivery of TIPE2 inhibits breast cancer development and metastasis via CD8(+) T and NK cell-mediated antitumor responses.Mol Immunol. 2017 May;85:230-237. doi: 10.1016/j.molimm.2017.03.007. Epub 2017 Mar 15.
29	TIPE? suppresses growth and aggressiveness of hepatocellular carcinoma cells through downregulation of the phosphoinositide 3kinase/AKT signaling pathway.Mol Med Rep. 2018 May;17(5):7017-7026. doi: 10.3892/mmr.2018.8789. Epub 2018 Mar 20.
30	Upregulation of Tumor Necrosis Factor--Induced Protein 8-Like 2 mRNA Is Negatively Correlated with Serum Concentrations of Tumor Necrosis Factor- and Interleukin 6 in Type 2 Diabetes Mellitus.J Diabetes Res. 2017;2017:4802319. doi: 10.1155/2017/4802319. Epub 2017 May 24.
31	Elevated Tumor Necrosis Factor-a-induced Protein 8-like 2 mRNA from Peripheral Blood Mononuclear Cells in Patients with Acute Ischemic Stroke.Int J Med Sci. 2018 Nov 22;15(14):1713-1722. doi: 10.7150/ijms.27817. eCollection 2018.
32	Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
33	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.