title: Pretreatment with TCDD exacerbates liver injury from Concanavalin A: critical role for NK cells.
abstract: For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6 mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response.
authors: Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
authors: Aaron M
authors: AM
authors: Fullerton
authors: Robert A
authors: RA
authors: Roth
authors: Patricia E
authors: PE
authors: Ganey
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018925:Chemokines / Q000097:blood; D003208:Concanavalin A / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D037181:Lectins, C-Type / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013997:Time Factors; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D055610:Antigens, CD1d; D000945:Antigens, Differentiation, T-Lymphocyte; D018925:Chemokines; D003208:Concanavalin A; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D000072317:Polychlorinated Dibenzodioxins; D000099192:CD69 Antigens; C584692:CD1d antigen, mouse; C064658:RAG-1 protein
keywords: autoimmune; chemokines; dioxin; inflammation; liver.
references: Cell Mol Immunol. 2007 Aug;4(4):241-52
references: 17764614
references: Immunology. 2010 Dec;131(4):451-8
references: 21039469
references: Hepatology. 2011 Apr;53(4):1270-81
references: 21400555
references: Toxicol Lett. 1997 Feb 7;90(2-3):145-53
references: 9067482
references: J Immunol. 2008 Mar 15;180(6):4308-15
references: 18322244
references: Trends Immunol. 2011 Oct;32(10):452-60
references: 21839682
references: Am J Physiol Lung Cell Mol Physiol. 2005 Jul;289(1):L111-24
references: 15792965
references: Toxicol Lett. 1992 May;60(3):247-56
references: 1595084
references: J Gastroenterol Hepatol. 2003 Oct;18(10):1118-28
references: 12974897
references: Toxicol Sci. 2011 Apr;120(2):507-18
references: 21245496
references: Immunity. 2002 Jun;16(6):779-90
references: 12121660
references: Trends Immunol. 2009 Sep;30(9):447-54
references: 19699679
references: Eur J Immunol. 2000 Apr;30(4):985-92
references: 10760785
references: Annu Rev Pharmacol Toxicol. 1982;22:517-54
references: 6282188
references: Toxicol Sci. 2008 Mar;102(1):61-75
references: 18042819
references: Eur J Immunol. 1998 Dec;28(12):4105-13
references: 9862346
references: J Exp Med. 2000 Jan 3;191(1):105-14
references: 10620609
references: Cell Immunol. 2008 Jan;251(1):25-30
references: 18374909
references: J Autoimmun. 2006 Jun;26(4):232-40
references: 16730427
references: Arch Toxicol. 1988;62(5):359-68
references: 3242446
references: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2367-72
references: 10681432
references: BMC Genomics. 2011 Jul 15;12:365
references: 21762485
references: J Immunol. 1995 Aug 15;155(4):2158-64
references: 7636264
references: Cell Immunol. 2005 Jan;233(1):23-9
references: 15893298
references: Toxicol Sci. 2011 Mar;120 Suppl 1:S171-91
references: 20952503
references: J Hepatol. 2001 Aug;35(2):217-24
references: 11580144
references: Environ Health Perspect. 1995 Dec;103 Suppl 9:47-53
references: 8635439
references: Nature. 2008 May 1;453(7191):65-71
references: 18362915
references: Toxicol Sci. 2005 Jun;85(2):1048-63
references: 15800033
references: J Autoimmun. 2010 Feb;34(1):7-14
references: 19766456
references: Immunology. 2009 Jul;127(3):299-311
references: 19538249
references: J Immunol. 1997 Aug 1;159(3):1537-42
references: 9233653
references: Toxicol Appl Pharmacol. 1994 Aug;127(2):331-5
references: 8048078
references: Toxicol Appl Pharmacol. 2002 Dec 1;185(2):146-52
references: 12490139
references: Gastroenterology. 2010 Jul;139(1):58-72.e4
references: 20451521
references: Immunol Cell Biol. 2002 Feb;80(1):113-6
references: 11869369
references: Hepatology. 1996 Oct;24(4):824-9
references: 8855184
references: Biochem Pharmacol. 2009 Feb 15;77(4):746-60
references: 19100241
references: Am J Pathol. 2000 Nov;157(5):1671-83
references: 11073826
references: Exp Toxicol Pathol. 1996 Jul;48(5):471-6
references: 8765693
references: Toxicol Appl Pharmacol. 2003 Jul 15;190(2):120-34
references: 12878042
references: J Immunol. 2002 Apr 15;168(8):3763-70
references: 11937527
references: Reprod Toxicol. 2011 Apr;31(3):312-8
references: 20728533
references: J Immunol. 2004 Jan 1;172(1):45-53
references: 14688308
references: Nat Immunol. 2012 Jul 19;13(8):722-8
references: 22814351
references: World J Gastroenterol. 2012 Jan 14;18(2):119-25
references: 22253517
references: Rheumatology (Oxford). 2008 Sep;47(9):1317-22
references: 18617548
references: J Clin Invest. 1992 Jul;90(1):196-203
references: 1634608
references: Hepatology. 2000 Oct;32(4 Pt 1):728-33
references: 11003616
references: J Immunol. 1999 Nov 1;163(9):4647-50
references: 10528160
references: Birth Defects Res A Clin Mol Teratol. 2009 Oct;85(10):828-36
references: 19572409
references: Toxicol Sci. 2003 Mar;72(1):43-56
references: 12604833
references: Gastroenterology. 1997 Oct;113(4):1315-22
references: 9322527
references: Food Addit Contam. 2000 Apr;17(4):275-88
references: 10912242
references: Exp Cell Res. 1996 Nov 25;229(1):137-46
references: 8940257
references: Immunotherapy. 2009 Jul;1(4):539-47
references: 20174617
references: Arch Biochem Biophys. 2007 May 15;461(2):169-75
references: 17320037
references: Drug Metab Dispos. 1986 Jan-Feb;14(1):34-40
references: 2868862
references: Toxicol Appl Pharmacol. 1995 Feb;130(2):197-208
references: 7871533
references: Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1260-7
references: 21441140
references: Toxicol Appl Pharmacol. 2013 Jan 15;266(2):317-27
references: 23164664
references: Nucleic Acids Res. 2004 Aug 24;32(15):4512-23
references: 15328365
references: J Mol Med (Berl). 2010 Dec;88(12):1289-98
references: 20848269
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5498-503
references: 10792025
references: Front Physiol. 2012 Oct 19;3:56
references: 23091461
references: Toxicol Appl Pharmacol. 2013 Mar 1;267(2):184-91
references: 23238561
references: Hepat Res Treat. 2010;2010:248157
references: 21253536
references: Toxicol Appl Pharmacol. 1993 Mar;119(1):100-7
references: 7682342