Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNX0JD0)

• DOT Name: C-C motif chemokine 13 (CCL13)
• Synonyms: CK-beta-10; Monocyte chemoattractant protein 4; Monocyte chemotactic protein 4; MCP-4; NCC-1; Small-inducible cytokine A13
• Gene Name: CCL13
• Related Disease:
  Multiple sclerosis
  Subarachnoid hemorrhage
  Allergic rhinitis
  Asthma
  Atopic dermatitis
  Behcet disease
  Bronchopulmonary dysplasia
  Glomerulonephritis
  Hepatitis B virus infection
  Lung cancer
  Lung carcinoma
  Nasal polyp
  Nephrotic syndrome
  Neuromyelitis optica
  Osteoarthritis
  Pneumonia
  Pneumonitis
  Respiratory disease
  Retinal vein occlusion
  Rheumatoid arthritis
  Rhinitis
  Sarcoidosis
  Uveitis
  B-cell lymphoma
  Chronic obstructive pulmonary disease
  High blood pressure
  Small lymphocytic lymphoma
  Acute myelogenous leukaemia
  Glioblastoma multiforme
  Coronary heart disease
  Post-traumatic stress disorder
• UniProt ID: CCL13_HUMAN
• PDB ID: 2RA4
• Pfam ID: PF00048
• Sequence:
  MKVSAVLLCLLLMTAAFNPQGLAQPDALNVPSTCCFTFSSKKISLQRLKSYVITTSRCPQ
  KAVIFRTKLGKEICADPKEKWVQNYMKHLGRKAHTLKT
• Function: Chemotactic factor that attracts monocytes, lymphocytes, basophils and eosinophils, but not neutrophils. Signals through CCR2B and CCR3 receptors. Plays a role in the accumulation of leukocytes at both sides of allergic and non-allergic inflammation. May be involved in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis. May play a role in the monocyte attraction in tissues chronically exposed to exogenous pathogens.
• Tissue Specificity: Widely expressed. Found in small intestine, thymus, colon, lung, trachea, stomach and lymph node. Low levels seen in the pulmonary artery smooth muscle cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  NF-kappa B sig.ling pathway (hsa04064)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Genetic Variation	[2]
Allergic rhinitis	DIS3U9HN	Strong	Altered Expression	[3]
Asthma	DISW9QNS	Strong	Altered Expression	[4]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[5]
Behcet disease	DISSYMBS	Strong	Altered Expression	[6]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[7]
Glomerulonephritis	DISPZIQ3	Strong	Altered Expression	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[10]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[10]
Nasal polyp	DISLP3XE	Strong	Biomarker	[11]
Nephrotic syndrome	DISSPSC2	Strong	Altered Expression	[12]
Neuromyelitis optica	DISBFGKL	Strong	Altered Expression	[13]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[14]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[15]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[15]
Respiratory disease	DISGGAGJ	Strong	Biomarker	[16]
Retinal vein occlusion	DISSVWOE	Strong	Altered Expression	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[1]
Rhinitis	DISKLMN7	Strong	Altered Expression	[3]
Sarcoidosis	DISE5B8Z	Strong	Altered Expression	[6]
Uveitis	DISV0RYS	Strong	Altered Expression	[6]
B-cell lymphoma	DISIH1YQ	moderate	Biomarker	[18]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[19]
High blood pressure	DISY2OHH	moderate	Altered Expression	[19]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[18]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Biomarker	[20]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[21]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[22]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of C-C motif chemokine 13 (CCL13).	[24]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of C-C motif chemokine 13 (CCL13).	[25]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of C-C motif chemokine 13 (CCL13).	[26]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of C-C motif chemokine 13 (CCL13).	[27]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of C-C motif chemokine 13 (CCL13).	[28]
Prednisone	DM2HG4X	Approved	Prednisone decreases the expression of C-C motif chemokine 13 (CCL13).	[29]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of C-C motif chemokine 13 (CCL13).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of C-C motif chemokine 13 (CCL13).	[24]

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 C-C motif chemokine 13 (CCL13).	[30]

References

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• [5] Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.Ann Allergy Asthma Immunol. 2020 Jan;124(1):70-78. doi: 10.1016/j.anai.2019.10.013. Epub 2019 Oct 14.
• [6] The CC chemokines CCL8, CCL13 and CCL20 are local inflammatory biomarkers of HLA-B27-associated uveitis.Acta Ophthalmol. 2019 Feb;97(1):e122-e128. doi: 10.1111/aos.13835. Epub 2018 Sep 21.
• [7] Increased serum Th2 chemokine levels are associated with bronchopulmonary dysplasia in premature infants.Eur J Pediatr. 2019 Jan;178(1):81-87. doi: 10.1007/s00431-018-3266-z. Epub 2018 Oct 15.
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• [9] Interferon-alpha restrains growth and invasive potential of hepatocellular carcinoma induced by hepatitis B virus X protein.World J Gastroenterol. 2008 Sep 28;14(36):5564-9; discussion 5568. doi: 10.3748/wjg.14.5564.
• [10] Circulating Inflammation Proteins Associated With Lung Cancer in African Americans.J Thorac Oncol. 2019 Jul;14(7):1192-1203. doi: 10.1016/j.jtho.2019.03.014. Epub 2019 Apr 3.
• [11] Expression of MCP-4 by TLR ligand-stimulated nasal polyp fibroblasts.Acta Otolaryngol. 2007 Dec;127(12):1304-9. doi: 10.1080/00016480701242444.
• [12] Gene expression profiling of peripheral blood mononuclear cells from patients with minimal change nephrotic syndrome by cDNA microarrays.Am J Nephrol. 2008;28(4):539-47. doi: 10.1159/000114098. Epub 2008 Jan 25.
• [13] Elevated Plasma Chemokines for Eosinophils in Neuromyelitis Optica Spectrum Disorders during Remission.Front Neurol. 2018 Feb 12;9:44. doi: 10.3389/fneur.2018.00044. eCollection 2018.
• [14] Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis.Rheumatology (Oxford). 2006 Apr;45(4):421-4. doi: 10.1093/rheumatology/kei209. Epub 2005 Nov 22.
• [15] Eotaxin and monocyte chemotactic protein-4 mRNA expression in small airways of asthmatic and nonasthmatic individuals.J Allergy Clin Immunol. 1999 Mar;103(3 Pt 1):476-83. doi: 10.1016/s0091-6749(99)70474-4.
• [16] Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines.J Clin Invest. 1997 Mar 1;99(5):926-36. doi: 10.1172/JCI119257.
• [17] Comprehensive analysis of vitreous chemokines involved in ischemic retinal vein occlusion.Mol Vis. 2019 Nov 15;25:756-765. eCollection 2019.
• [18] Single-nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of non-Hodgkin lymphoma.Cancer Epidemiol Biomarkers Prev. 2013 Jul;22(7):1332-5. doi: 10.1158/1055-9965.EPI-13-0328. Epub 2013 May 2.
• [19] Serum cytokine profiles in patients with chronic obstructive pulmonary disease associated pulmonary hypertension identified using protein array.Cytokine. 2018 Nov;111:342-349. doi: 10.1016/j.cyto.2018.09.005. Epub 2018 Sep 28.
• [20] The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells.Br J Haematol. 2009 Jun;145(6):761-74. doi: 10.1111/j.1365-2141.2009.07691.x. Epub 2009 Apr 20.
• [21] Molecular profiling of the tumor microenvironment in glioblastoma patients: correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival.Biosci Rep. 2019 Jun 20;39(6):BSR20182361. doi: 10.1042/BSR20182361. Print 2019 Jun 28.
• [22] Integrative miRNA and whole-genome analyses of epicardial adipose tissue in patients with coronary atherosclerosis.Cardiovasc Res. 2016 Feb 1;109(2):228-39. doi: 10.1093/cvr/cvv266. Epub 2015 Dec 8.
• [23] The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder.Transl Psychiatry. 2017 Feb 7;7(2):e1025. doi: 10.1038/tp.2016.285.
• [24] Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders. J Mol Endocrinol. 2015 Jun;54(3):289-303.
• [25] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [26] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [27] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [28] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [29] Alterations in eotaxin, monocyte chemoattractant protein-4, interleukin-5, and interleukin-13 after systemic steroid treatment for nasal polyps. Otolaryngol Head Neck Surg. 2004 Nov;131(5):585-9. doi: 10.1016/j.otohns.2004.05.028.
• [30] 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.
• [31] Chemicals with weak skin sensitizing properties can be identified using low-density microarrays on immature dendritic cells. Toxicol Lett. 2007 Nov 1;174(1-3):98-109. doi: 10.1016/j.toxlet.2007.08.015. Epub 2007 Sep 5.