Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis.
The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.
Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, USA.
Cheri L
CL
Lamb
Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, USA.
Giovan N
GN
Cholico
Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
Daniel E
DE
Perkins
Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
Michael T
MT
Fewkes
Department of Biological Sciences, Boise State University, Boise, ID 83725, USA; Biomolecular Research Center, Boise State University, Boise, ID 83725, USA.
Julia Thom
JT
Oxford
Department of Mechanical and Biomedical Engineering, Boise State University, Boise, ID 83725, USA.
Trevor J
TJ
Lujan
Department of Mechanical and Biomedical Engineering, Boise State University, Boise, ID 83725, USA.
Erica E
EE
Morrill
Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, USA; Department of Biological Sciences, Boise State University, Boise, ID 83725, USA.
Kristen A
0000-0001-8872-0579
KA
Mitchell
Biomech Model Mechanobiol. 2016 Dec;15(6):1467-1478
26946162
Biochem J. 1987 May 15;244(1):75-9
3663119
FEBS Lett. 2007 Jul 31;581(19):3608-15
17412325
Cell Signal. 2012 Aug;24(8):1665-76
22560882
J Endocrinol. 2011 May;209(2):139-51
21307119
Cell Tissue Res. 2003 Mar;311(3):373-82
12658445
J Cell Biochem. 2003 Mar 1;88(4):660-72
12577300
Toxicol Sci. 2005 Nov;88(1):231-41
16120747
J Immunol. 2007 Apr 15;178(8):5288-95
17404313
Toxicol Appl Pharmacol. 2006 Feb 1;210(3):212-24
15982688
PLoS One. 2014 Oct 13;9(10):e110405
25310107
Toxicol Appl Pharmacol. 2016 Nov 15;311:42-51
27693115
Science. 1995 May 5;268(5211):722-6
7732381
Biochim Biophys Acta. 2013 Jul;1832(7):876-83
23149387
Annu Rev Pharmacol Toxicol. 2000;40:519-61
10836146
Biochem Biophys Res Commun. 2000 Jun 7;272(2):441-8
10833433
Biochem Pharmacol. 2009 Mar 15;77(6):947-56
19027718
J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53
15788652
Fertil Steril. 2005 Jul;84(1):67-74
16009159
Toxicol Sci. 2008 Feb;101(2):321-30
17975115
Fibrogenesis Tissue Repair. 2012 Jun 06;5(Suppl 1):S26
23259590
Matrix Biol. 2015 May-Jul;44-46:247-54
25805621
J Biol Chem. 2015 Feb 6;290(6):3639-46
25525267
J Cell Physiol. 1999 Oct;181(1):96-106
10457357
Nat Protoc. 2008;3(6):1101-8
18546601
Toxicol Appl Pharmacol. 2005 Aug 22;207 (1):39-58
16054899
J Pharmacol Exp Ther. 2013 Jun;345(3):419-29
23512538
J Pathol. 2015 Jan;235(1):101-12
25186463
Toxicol Appl Pharmacol. 1995 Jul;133(1):34-42
7597708
Arch Toxicol. 2002 Jun;76(5-6):360-6
12107654
J Histochem Cytochem. 2010 Jan;58(1):29-39
19755718
Clin Liver Dis. 2008 Nov;12(4):759-68, viii
18984465
Biol Chem. 2006 Sep;387(9):1159-73
16972783
J Cell Biochem. 2006 Aug 15;98(6):1436-49
16518859
Am J Physiol Gastrointest Liver Physiol. 2015 May 15;308(10):G807-30
25767261
Nat Commun. 2013;4:2823
24264436
Toxicol Res (Camb). 2015 Sep 1;4(5):1143-1158
26783425
Toxicol Sci. 2002 Oct;69(2):409-23
12377990
Cancer Lett. 2005 Jul 8;225(1):159-66
15922868
Histochem J. 1979 Jul;11(4):447-55
91593
J Cell Sci. 2009 Jun 1;122(Pt 11):1823-33
19435800
Toxicol Appl Pharmacol. 2004 Jan 1;194(1):79-89
14728982
J Clin Invest. 2005 Jan;115(1):56-65
15630444
Trends Mol Med. 2007 Feb;13(2):45-53
17169614
Toxicology. 2006 Sep 21;226(2-3):197-207
16920245
Toxicol Appl Pharmacol. 1998 Nov;153(1):109-18
9875305
J Hepatol. 1999 Jan;30(1):48-60
9927150
Mol Pharmacol. 2012 Mar;81(3):338-47
22113079
Cardiovasc Res. 2006 Feb 15;69(3):562-73
16405877
Toxicol Sci. 2006 Jul;92 (1):254-69
16443690
Toxicol Sci. 2007 Jan;95(1):215-26
17003102
Electrophoresis. 2012 Jan;33(2):366-9
22222980
J Biol Chem. 1996 Dec 13;271(50):31767-70
8943211
FASEB J. 2016 Apr;30(4):1599-609
26700732
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17858-63
16301529
Toxicol Sci. 2014 Jan;137(1):114-24
24154488
Proc Natl Acad Sci U S A. 2012 Nov 13;109 (46):E3186-95
23100531
Toxicology. 2016 Feb 17;344-346:26-33
26860701
J Cell Biol. 1997 Feb 10;136(3):729-43
9024701
Biochim Biophys Acta. 2010 Jan;1803(1):39-54
19800373
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13243-7
22847422
Toxicol Appl Pharmacol. 1996 Sep;140(1):173-9
8806883
Crit Rev Eukaryot Gene Expr. 2008;18(3):207-50
18540824
Lab Invest. 1998 Aug;78(8):967-72
9714184
Endocr J. 2004 Dec;51(6):569-77
15644576
Arch Toxicol. 2002 Jul;76(7):404-13
12111005
Adv Wound Care (New Rochelle). 2015 Apr 1;4(4):225-234
25945285
Cell Biosci. 2011 Apr 04;1(1):14
21711826
J Histochem Cytochem. 2012 Apr;60(4):262-8
22260996
Cardiovasc Toxicol. 2004;4(4):363-73
15531779
J Cell Sci. 2002 Oct 1;115(Pt 19):3719-27
12235282
J Biol Chem. 2000 Jan 28;275(4):2247-50
10644669
Mol Pharmacol. 1998 Aug;54(2):313-21
9687573
Gastroenterology. 1979 Apr;76(4):710-9
421999
Mol Cell Biol. 2007 Sep;27(17):6127-39
17606626
Physiol Rev. 2008 Jan;88(1):125-72
18195085
Annu Rev Pharmacol Toxicol. 1995;35:307-40
7598497
Matrix Biol. 2015 May-Jul;44-46:147-56
25599939
Hepatology. 1999 Oct;30(4):944-50
10498646
J Biol Chem. 2004 Jun 11;279(24):25284-93
15075337
J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200
21123617