Details of Drug Off-Target (DOT)

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

• DOT Name: Interleukin-6 (IL6)
• Synonyms: IL-6; B-cell stimulatory factor 2; BSF-2; CTL differentiation factor; CDF; Hybridoma growth factor; Interferon beta-2; IFN-beta-2
• Gene Name: IL6
• UniProt ID: IL6_HUMAN
• PDB ID: 1ALU; 1IL6; 1P9M; 2IL6; 4CNI; 4J4L; 4NI7; 4NI9; 4O9H; 4ZS7; 5FUC; 7NXZ; 8D82
• Pfam ID: PF00489
• Sequence:
  MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYI
  LDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLL
  EFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQ
  AQNQWLQDMTTHLILRSFKEFLQSSLRALRQM
• Function: Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway (Probable). The interaction with the membrane-bound IL6R and IL6ST stimulates 'classic signaling', whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable); IL6 is a potent inducer of the acute phase response. Rapid production of IL6 contributes to host defense during infection and tissue injury, but excessive IL6 synthesis is involved in disease pathology. In the innate immune response, is synthesized by myeloid cells, such as macrophages and dendritic cells, upon recognition of pathogens through toll-like receptors (TLRs) at the site of infection or tissue injury (Probable). In the adaptive immune response, is required for the differentiation of B cells into immunoglobulin-secreting cells. Plays a major role in the differentiation of CD4(+) T cell subsets. Essential factor for the development of T follicular helper (Tfh) cells that are required for the induction of germinal-center formation. Required to drive naive CD4(+) T cells to the Th17 lineage. Also required for proliferation of myeloma cells and the survival of plasmablast cells; Acts as an essential factor in bone homeostasis and on vessels directly or indirectly by induction of VEGF, resulting in increased angiogenesis activity and vascular permeability. Induces, through 'trans-signaling' and synergistically with IL1B and TNF, the production of VEGF. Involved in metabolic controls, is discharged into the bloodstream after muscle contraction increasing lipolysis and improving insulin resistance. 'Trans-signaling' in central nervous system also regulates energy and glucose homeostasis. Mediates, through GLP-1, crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. Also acts as a myokine (Probable). Plays a protective role during liver injury, being required for maintenance of tissue regeneration. Also has a pivotal role in iron metabolism by regulating HAMP/hepcidin expression upon inflammation or bacterial infection. Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation-induced epithelial regeneration.
• Tissue Specificity: Produced by skeletal muscle.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Antifolate resistance (hsa01523)
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  HIF-1 sig.ling pathway (hsa04066)
  FoxO sig.ling pathway (hsa04068)
  PI3K-Akt sig.ling pathway (hsa04151)
  Cellular senescence (hsa04218)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  Cytosolic D.-sensing pathway (hsa04623)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  IL-17 sig.ling pathway (hsa04657)
  Th17 cell differentiation (hsa04659)
  TNF sig.ling pathway (hsa04668)
  Intesti.l immune network for IgA production (hsa04672)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Inflammatory bowel disease (hsa05321)
  Rheumatoid arthritis (hsa05323)
  Graft-versus-host disease (hsa05332)
  Hypertrophic cardiomyopathy (hsa05410)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MAPK3 (ERK1) activation (R-HSA-110056)
  MAPK1 (ERK2) activation (R-HSA-112411)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Interleukin-10 signaling (R-HSA-6783783)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Post-translational protein phosphorylation (R-HSA-8957275)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  CD163 mediating an anti-inflammatory response (R-HSA-9662834)
  Interleukin-6 signaling (R-HSA-1059683)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 13 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Interleukin-6 (IL6) increases the response to substance of Dexamethasone.	[87]
Irinotecan	DMP6SC2	Approved	Interleukin-6 (IL6) decreases the response to substance of Irinotecan.	[88]
DTI-015	DMXZRW0	Approved	Interleukin-6 (IL6) affects the response to substance of DTI-015.	[89]
Fenofibrate	DMFKXDY	Approved	Interleukin-6 (IL6) affects the response to substance of Fenofibrate.	[90]
Enzalutamide	DMGL19D	Approved	Interleukin-6 (IL6) decreases the response to substance of Enzalutamide.	[91]
Clopidogrel	DMOL54H	Approved	Interleukin-6 (IL6) increases the response to substance of Clopidogrel.	[88]
Enalapril	DMNFUZR	Approved	Interleukin-6 (IL6) affects the response to substance of Enalapril.	[92]
Midazolam	DMXOELT	Approved	Interleukin-6 (IL6) increases the Cytokine release syndrome ADR of Midazolam.	[93]
Pentoxifylline	DMU3DNC	Approved	Interleukin-6 (IL6) increases the Inflammation ADR of Pentoxifylline.	[93]
Uracil mustard	DMHL7OB	Approved	Interleukin-6 (IL6) increases the Skin and subcutaneous tissue disorders ADR of Uracil mustard.	[93]
Oseltamivir	DMGO72P	Approved	Interleukin-6 (IL6) decreases the response to substance of Oseltamivir.	[88]
Rituximab	DM1YVZT	Approved	Interleukin-6 (IL6) increases the Adverse drug reaction ADR of Rituximab.	[93]
1,2,3,4-tetrahydroisoquinoline	DMZGCEQ	Investigative	Interleukin-6 (IL6) decreases the response to substance of 1,2,3,4-tetrahydroisoquinoline.	[95]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Interleukin-6 (IL6) increases the uptake of Manganese.	[94]

81 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-6 (IL6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-6 (IL6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interleukin-6 (IL6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interleukin-6 (IL6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-6 (IL6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interleukin-6 (IL6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Interleukin-6 (IL6).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Interleukin-6 (IL6).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interleukin-6 (IL6).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interleukin-6 (IL6).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interleukin-6 (IL6).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Interleukin-6 (IL6).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Interleukin-6 (IL6).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Interleukin-6 (IL6).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Interleukin-6 (IL6).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Interleukin-6 (IL6).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Interleukin-6 (IL6).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-6 (IL6).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Interleukin-6 (IL6).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Interleukin-6 (IL6).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interleukin-6 (IL6).	[21]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interleukin-6 (IL6).	[22]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interleukin-6 (IL6).	[23]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Interleukin-6 (IL6).	[24]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Interleukin-6 (IL6).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interleukin-6 (IL6).	[26]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Interleukin-6 (IL6).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Interleukin-6 (IL6).	[3]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Interleukin-6 (IL6).	[28]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Interleukin-6 (IL6).	[29]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Interleukin-6 (IL6).	[31]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Interleukin-6 (IL6).	[18]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Interleukin-6 (IL6).	[32]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Interleukin-6 (IL6).	[33]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Interleukin-6 (IL6).	[34]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Interleukin-6 (IL6).	[35]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Interleukin-6 (IL6).	[18]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Interleukin-6 (IL6).	[18]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Interleukin-6 (IL6).	[37]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Interleukin-6 (IL6).	[38]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Interleukin-6 (IL6).	[39]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Interleukin-6 (IL6).	[40]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Interleukin-6 (IL6).	[42]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Interleukin-6 (IL6).	[43]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Interleukin-6 (IL6).	[45]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Interleukin-6 (IL6).	[46]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Interleukin-6 (IL6).	[47]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Interleukin-6 (IL6).	[48]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Interleukin-6 (IL6).	[50]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Interleukin-6 (IL6).	[52]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Interleukin-6 (IL6).	[53]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Interleukin-6 (IL6).	[54]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Interleukin-6 (IL6).	[55]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Interleukin-6 (IL6).	[18]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Interleukin-6 (IL6).	[58]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Interleukin-6 (IL6).	[53]
Ritonavir	DMU764S	Approved	Ritonavir increases the expression of Interleukin-6 (IL6).	[50]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Interleukin-6 (IL6).	[18]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Interleukin-6 (IL6).	[59]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of Interleukin-6 (IL6).	[61]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Interleukin-6 (IL6).	[62]
Bosentan	DMIOGBU	Approved	Bosentan increases the expression of Interleukin-6 (IL6).	[63]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Interleukin-6 (IL6).	[64]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the expression of Interleukin-6 (IL6).	[66]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Interleukin-6 (IL6).	[67]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of Interleukin-6 (IL6).	[71]
Bleomycin	DMNER5S	Approved	Bleomycin increases the expression of Interleukin-6 (IL6).	[72]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of Interleukin-6 (IL6).	[73]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Interleukin-6 (IL6).	[74]
Estriol	DMOEM2I	Approved	Estriol decreases the expression of Interleukin-6 (IL6).	[7]
Ergotidine	DM78IME	Approved	Ergotidine increases the expression of Interleukin-6 (IL6).	[76]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Interleukin-6 (IL6).	[37]
Nelfinavir mesylate	DMFX6G8	Approved	Nelfinavir mesylate increases the expression of Interleukin-6 (IL6).	[50]
Nicotinamide	DMUPE07	Approved	Nicotinamide decreases the expression of Interleukin-6 (IL6).	[78]
Epirubicin	DMPDW6T	Approved	Epirubicin increases the expression of Interleukin-6 (IL6).	[79]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the expression of Interleukin-6 (IL6).	[80]
Lidocaine	DML4ZOT	Approved	Lidocaine decreases the expression of Interleukin-6 (IL6).	[81]
Salbutamol	DMN9CWF	Approved	Salbutamol increases the expression of Interleukin-6 (IL6).	[82]
Pantothenic acid	DM091H2	Approved	Pantothenic acid increases the expression of Interleukin-6 (IL6).	[83]
Dobutamine	DMD1B8Z	Approved	Dobutamine increases the expression of Interleukin-6 (IL6).	[84]
Stavudine	DM6DEK9	Approved	Stavudine increases the expression of Interleukin-6 (IL6).	[50]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the secretion of Interleukin-6 (IL6).	[30]
Nicotine	DMWX5CO	Approved	Nicotine decreases the secretion of Interleukin-6 (IL6).	[36]
Menthol	DMG2KW7	Approved	Menthol increases the secretion of Interleukin-6 (IL6).	[41]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the secretion of Interleukin-6 (IL6).	[49]
Vinblastine	DM5TVS3	Approved	Vinblastine increases the stability of Interleukin-6 (IL6).	[51]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the secretion of Interleukin-6 (IL6).	[56]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the secretion of Interleukin-6 (IL6).	[57]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the secretion of Interleukin-6 (IL6).	[60]
Ardeparin	DMYRX8B	Approved	Ardeparin increases the secretion of Interleukin-6 (IL6).	[65]
Melatonin	DMKWFBT	Approved	Melatonin decreases the secretion of Interleukin-6 (IL6).	[68]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the secretion of Interleukin-6 (IL6).	[69]
Morphine	DMRMS0L	Approved	Morphine increases the secretion of Interleukin-6 (IL6).	[70]
Nevirapine	DM6HX9B	Approved	Nevirapine decreases the secretion of Interleukin-6 (IL6).	[75]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the secretion of Interleukin-6 (IL6).	[75]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the secretion of Interleukin-6 (IL6).	[77]
Flucloxacillin	DMNUWST	Approved	Flucloxacillin increases the secretion of Interleukin-6 (IL6).	[69]
Furosemide	DMMQ8ZG	Approved	Furosemide decreases the secretion of Interleukin-6 (IL6).	[85]
Imiquimod	DM1TMA3	Approved	Imiquimod increases the secretion of Interleukin-6 (IL6).	[86]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine affects the methylation of Interleukin-6 (IL6).	[44]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Differential regulation of Toll-like receptor and CD14 pathways by retinoids and corticosteroids in human sebocytes. Dermatology. 2006;213(3):266. doi: 10.1159/000095056.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] microRNA-486-5p is implicated in the cisplatin-induced apoptosis and acute inflammation response of renal tubular epithelial cells by targeting HAT1. J Biochem Mol Toxicol. 2022 Jun;36(6):e23039. doi: 10.1002/jbt.23039. Epub 2022 Mar 13.
• [7] Atheroprotective effect of estriol and estrone sulfate on human vascular smooth muscle cells. J Steroid Biochem Mol Biol. 2000 Jan-Feb;72(1-2):71-8. doi: 10.1016/s0960-0760(99)00149-1.
• [8] Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions. Environ Toxicol. 2022 Aug;37(8):1831-1839. doi: 10.1002/tox.23530. Epub 2022 Apr 1.
• [9] Inhibitory effect of quercetin on tryptase and interleukin-6 release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line. Clin Exp Med. 2006 Dec;6(4):150-6. doi: 10.1007/s10238-006-0114-7.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells. Blood. 2003 Jun 1;101(11):4576-82. doi: 10.1182/blood-2002-09-2986. Epub 2003 Jan 30.
• [12] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [13] Calcitriol treatment attenuates inflammation and oxidative stress in hemodialysis patients with secondary hyperparathyroidism. Tohoku J Exp Med. 2011 Mar;223(3):153-9. doi: 10.1620/tjem.223.153.
• [14] Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice. Mol Cancer Ther. 2009 Jun;8(6):1596-605. doi: 10.1158/1535-7163.MCT-08-1004. Epub 2009 Jun 9.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [17] Carbamazepine-induced thrombocytopenia defined by a challenge test. Am J Hematol. 1999 Sep;62(1):52-5. doi: 10.1002/(sici)1096-8652(199909)62:1<52::aid-ajh9>3.0.co;2-e.
• [18] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [19] Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther. 2007 Nov;6(11):3071-9. doi: 10.1158/1535-7163.MCT-07-0117.
• [20] Zoledronic acid effects interleukin-6 expression in hormone-independent prostate cancer cell lines. Int Braz J Urol. 2008 May-Jun;34(3):355-63; discussion 364. doi: 10.1590/s1677-55382008000300013.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] P38 MAPK, NF-B, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression. Chem Res Toxicol. 2022 Mar 21;35(3):422-430. doi: 10.1021/acs.chemrestox.1c00317. Epub 2022 Feb 11.
• [24] ERE-independent ERalpha target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005 Dec 21;245(1-2):53-9. doi: 10.1016/j.mce.2005.10.003. Epub 2005 Nov 17.
• [25] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [28] Combination chemotherapy increases cytotoxicity of multiple myeloma cells by modification of nuclear factor (NF)-B activity. Exp Hematol. 2013 Feb;41(2):209-18. doi: 10.1016/j.exphem.2012.10.002. Epub 2012 Oct 11.
• [29] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [30] Hydroquinone-induced apoptosis of human lymphocytes through caspase 9/3 pathway. Mol Biol Rep. 2012 Jun;39(6):6737-43. doi: 10.1007/s11033-012-1498-y.
• [31] Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome. Diabetes Care. 2006 May;29(5):1071-6. doi: 10.2337/diacare.2951071.
• [32] Acanthoic acid protectsagainst ethanol-induced liver injury: Possible role of AMPK activation and IRAK4 inhibition. Toxicol Lett. 2017 Nov 5;281:127-138. doi: 10.1016/j.toxlet.2017.09.020. Epub 2017 Sep 28.
• [33] Proinflammatory cytokines mediate the systemic inflammatory response associated with high-dose cytarabine treatment in children. Med Pediatr Oncol. 2001 Nov;37(5):459-64. doi: 10.1002/mpo.1230.
• [34] Aspirin induces apoptosis through the blockade of IL-6-STAT3 signaling pathway in human glioblastoma A172 cells. Biochem Biophys Res Commun. 2009 Sep 18;387(2):342-7. doi: 10.1016/j.bbrc.2009.07.022. Epub 2009 Jul 10.
• [35] Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. 2004 Feb 7;25(3):94-102. doi: 10.1016/j.cyto.2003.10.004.
• [36] Cigarette smoke extract interferes with placenta macrophage functions: A new mechanism to compromise placenta functions?. Reprod Toxicol. 2018 Jun;78:120-129. doi: 10.1016/j.reprotox.2018.04.009. Epub 2018 Apr 16.
• [37] Cytokine mRNA profiles in cultured human skin component cells exposed to various chemicals: a simulation model of epicutaneous stimuli induced by skin barrier perturbation in comparison with that due to exposure to haptens or irritant. J Dermatol Sci. 2001 Jun;26(2):85-93. doi: 10.1016/s0923-1811(00)00165-1.
• [38] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [39] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [40] An interleukin 1 receptor antagonist blocks the IL-1-induced IL-6 paracrine production through a prostaglandin E2-related mechanism in multiple myeloma. Stem Cells. 1995 Aug;13 Suppl 2:28-34.
• [41] Menthol in electronic cigarettes: A contributor to respiratory disease?. Toxicol Appl Pharmacol. 2020 Nov 15;407:115238. doi: 10.1016/j.taap.2020.115238. Epub 2020 Sep 17.
• [42] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [43] Mitomycin induces alveolar epithelial cell senescence by down-regulating GSK3 signaling. Toxicol Lett. 2021 Nov 1;352:61-69. doi: 10.1016/j.toxlet.2021.09.015. Epub 2021 Oct 5.
• [44] Hypomethylation of interleukin-4 and -6 promoters in T cells from systemic lupus erythematosus patients. Acta Pharmacol Sin. 2008 Jan;29(1):105-12. doi: 10.1111/j.1745-7254.2008.00739.x.
• [45] Cocaine dependence and acute cocaine induce decreases of monocyte proinflammatory cytokine expression across the diurnal period: autonomic mechanisms. J Pharmacol Exp Ther. 2007 Feb;320(2):507-15. doi: 10.1124/jpet.106.112797. Epub 2006 Oct 26.
• [46] Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1194-9. doi: 10.1161/01.atv.0000022694.16328.cc.
• [47] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [48] Rifampin protects human lung epithelial cells against cytotoxicity induced by clinical multi and pandrug-resistant Acinetobacter baumannii. J Infect Dis. 2011 Apr 15;203(8):1110-9. doi: 10.1093/infdis/jiq159. Epub 2011 Feb 28.
• [49] [Regulatory effects of mifepristone and progesterone on the secretion of interleukin-6 by cultured eutopic and etopic endometrial cells]. Zhonghua Fu Chan Ke Za Zhi. 2001 Oct;36(10):603-5.
• [50] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [51] Cytoskeletal architecture differentially controls post-transcriptional processing of IL-6 and IL-8 mRNA in airway epithelial-like cells. Exp Cell Res. 2006 May 15;312(9):1496-506. doi: 10.1016/j.yexcr.2006.01.010. Epub 2006 Feb 24.
• [52] Calcium-dependent and independent mechanisms of capsaicin receptor (TRPV1)-mediated cytokine production and cell death in human bronchial epithelial cells. J Biochem Mol Toxicol. 2005;19(4):266-75. doi: 10.1002/jbt.20084.
• [53] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [54] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [55] In vitro antitumoral effects of the steroid ouabain on human thyroid papillary carcinoma cell lines. Environ Toxicol. 2021 Jul;36(7):1338-1348. doi: 10.1002/tox.23130. Epub 2021 Mar 24.
• [56] Zinc induces chemokine and inflammatory cytokine release from human promonocytes. J Hazard Mater. 2011 Nov 30;196:335-41. doi: 10.1016/j.jhazmat.2011.09.035. Epub 2011 Sep 19.
• [57] Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs. Leukemia. 2005 Jul;19(7):1253-61. doi: 10.1038/sj.leu.2403776.
• [58] Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med. 2003 Apr;31(4):1068-74. doi: 10.1097/01.CCM.0000059646.89546.98.
• [59] Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: role of PGE2 in chemokine and cytokine expression by MoDCs. Int Immunol. 2005 Dec;17(12):1561-72. doi: 10.1093/intimm/dxh335. Epub 2005 Nov 22.
• [60] The effects of particulate wear debris, cytokines, and growth factors on the functions of MG-63 osteoblasts. J Bone Joint Surg Am. 2001 Feb;83(2):201-11. doi: 10.2106/00004623-200102000-00007.
• [61] Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers. Clin Cancer Res. 2004 Dec 15;10(24):8163-9.
• [62] Vitamin D3 treatment of Crohn's disease patients increases stimulated T cell IL-6 production and proliferation. Aliment Pharmacol Ther. 2010 Dec;32(11-12):1364-72. doi: 10.1111/j.1365-2036.2010.04463.x. Epub 2010 Sep 23.
• [63] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [64] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [65] Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules. Toxicol Lett. 2016 Jan 5;240(1):32-42. doi: 10.1016/j.toxlet.2015.10.005. Epub 2015 Oct 22.
• [66] Involvement of P2Y11 receptor in silica nanoparticles 30-induced IL-6 production by human keratinocytes. Toxicology. 2014 Aug 1;322:61-8. doi: 10.1016/j.tox.2014.03.010. Epub 2014 May 2.
• [67] The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function. Br J Anaesth. 2006 Dec;97(6):825-31. doi: 10.1093/bja/ael270. Epub 2006 Oct 9.
• [68] Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Arch Med Res. 2018 Aug;49(6):391-398. doi: 10.1016/j.arcmed.2018.12.004. Epub 2018 Dec 27.
• [69] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [70] Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. J Cell Biochem. 2010 Jul 1;110(4):834-45. doi: 10.1002/jcb.22592.
• [71] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [72] Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells. Cell Biol Toxicol. 2022 Aug;38(4):557-575. doi: 10.1007/s10565-022-09698-1. Epub 2022 Mar 10.
• [73] Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012 Dec;64(12):3856-66. doi: 10.1002/art.37691.
• [74] Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues. Toxicol Appl Pharmacol. 2010 May 1;244(3):354-65. doi: 10.1016/j.taap.2010.01.017. Epub 2010 Feb 6.
• [75] Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res. 2011 Aug;91(2):112-9. doi: 10.1016/j.antiviral.2011.04.018. Epub 2011 May 17.
• [76] Glycyrrhizin attenuates histamine-mediated MUC5AC upregulation, inflammatory cytokine production, and aquaporin 5 downregulation through suppressing the NF-B pathway in human nasal epithelial cells. Chem Biol Interact. 2018 Apr 1;285:21-26. doi: 10.1016/j.cbi.2018.02.010. Epub 2018 Feb 13.
• [77] Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation. 1999 Jul 6;100(1):48-54. doi: 10.1161/01.cir.100.1.48.
• [78] Downregulation of NF-kappaB activation in human keratinocytes by melanogenic inhibitors. J Dermatol Sci. 2003 May;31(3):193-201. doi: 10.1016/s0923-1811(03)00039-2.
• [79] Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers. Oncologist. 2007 Sep;12(9):1124-33. doi: 10.1634/theoncologist.12-9-1124.
• [80] Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension. 2006 Dec;48(6):1050-7. doi: 10.1161/01.HYP.0000248135.97380.76. Epub 2006 Oct 16.
• [81] [Influence of lidocaine on systemic inflammation in perioperative patients undergoing cardiopulmonary bypass]. Beijing Da Xue Xue Bao Yi Xue Ban. 2005 Dec 18;37(6):622-4.
• [82] Mechanisms by which S-albuterol induces human bronchial smooth muscle cell proliferation. Int Arch Allergy Immunol. 2008;146(4):321-33. doi: 10.1159/000121466. Epub 2008 Mar 21.
• [83] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
• [84] Myocardial ischemia induces interleukin-6 and tissue factor production in patients with coronary artery disease: a dobutamine stress echocardiography study. Circulation. 2005 Nov 22;112(21):3272-9. doi: 10.1161/CIRCULATIONAHA.104.532259. Epub 2005 Nov 14.
• [85] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [86] (9)-Tetrahydrocannabinol Suppresses Monocyte-Mediated Astrocyte Production of Monocyte Chemoattractant Protein 1 and Interleukin-6 in a Toll-Like Receptor 7-Stimulated Human Coculture. J Pharmacol Exp Ther. 2019 Oct;371(1):191-201. doi: 10.1124/jpet.119.260661. Epub 2019 Aug 5.
• [87] Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer. 2010 Jul;46(10):1848-55. doi: 10.1016/j.ejca.2010.03.026. Epub 2010 Apr 17.
• [88] Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol. 2007 Sep;72(3):686-94. doi: 10.1124/mol.107.036889. Epub 2007 May 30.
• [89] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [90] Interleukin-6 -174 G/C promoter polymorphism and effects of fenofibrate and simvastatin on inflammatory markers in hypercholesterolemic patients. Blood Coagul Fibrinolysis. 2006 Jan;17(1):35-8. doi: 10.1097/01.mbc.0000198052.65505.00.
• [91] Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate. 2015 Sep;75(13):1341-53. doi: 10.1002/pros.23015. Epub 2015 May 13.
• [92] Effect of enalapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the interleukin-6 gene. Am J Cardiol. 2004 Sep 1;94(5):564-9. doi: 10.1016/j.amjcard.2004.05.017.
• [93] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [94] Interleukin-6 enhances manganese accumulation in SH-SY5Y cells: implications of the up-regulation of ZIP14 and the down-regulation of ZnT10. Metallomics. 2014 Apr;6(4):944-9. doi: 10.1039/c3mt00362k.
• [95] Possible role of interleukin-6 in PC12 cell death induced by MPP+ and tetrahydroisoquinoline. J Pharmacol Sci. 2003 Dec;93(4):471-7. doi: 10.1254/jphs.93.471.