title: A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice.
abstract: A disintegrin and metalloproteinase 17 (ADAM17), or tumor necrosis factor (TNF)-α-converting enzyme, is a key metalloproteinase and physiological convertase for a number of putative targets that play critical roles in cytokine and growth factor signaling. These interdependent pathways are essential components of the signaling network that links liver function with the compensatory growth that occurs during liver regeneration following 2/3 partial hepatectomy (PH) or chemically induced hepatotoxicity. Despite identification of many soluble factors needed for efficient liver regeneration, very little is known about how such ligands are regulated in the liver. To directly study the role of ADAM17 in the liver, we employed two cell-specific ADAM17 knockout (KO) mouse models. Using lipopolysaccharide (LPS) as a robust stimulus for TNF release, we found attenuated levels of circulating TNF in myeloid-specific ADAM17 KO mice (ADAM17 m-KO) and, unexpectedly, in mice with hepatocyte-specific ADAM17 deletion (ADAM17 h-KO), indicating that ADAM17 expression in both cell types plays a role in TNF shedding. After 2/3 PH, induction of TNF, TNFR1, and amphiregulin (AR) was significantly attenuated in ADAM17 h-KO mice, implicating ADAM17 as the primary sheddase for these factors in the liver. Surprisingly, the extent and timing of hepatocyte proliferation were not affected after PH or carbon tetrachloride injection in ADAM17 h-KO or ADAM17 m-KO mice. We conclude that ADAM17 regulates TNF, TNFR1, and AR in the liver, and its expression in both hepatocytes and myeloid cells is important for TNF regulation after LPS injury or 2/3 PH, but is not required for liver regeneration.
authors: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors: Ryan S
authors: RS
authors: McMahan
authors: Kimberly J
authors: KJ
authors: Riehle
authors: Nelson
authors: N
authors: Fausto
authors: Jean S
authors: JS
authors: Campbell
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000818:Animals; D066255:EGF Family of Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006498:Hepatectomy; D007249:Inflammation / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: amphiregulin; lipopolysaccharide; partial hepatectomy; tumor necrosis factor receptor; tumor necrosis factor-α converting enzyme
references: Nature. 1997 Feb 20;385(6618):729-33
references: 9034190
references: J Hepatol. 2008 Aug;49(2):198-206
references: 18471922
references: Am J Pathol. 2010 Jan;176(1):2-13
references: 20019184
references: Immunity. 2005 Jan;22(1):93-104
references: 15664162
references: J Immunol. 1993 Nov 15;151(10):5554-62
references: 8228246
references: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1441-6
references: 9037072
references: J Immunol. 2006 Feb 15;176(4):2522-8
references: 16456013
references: Semin Cell Dev Biol. 2002 Dec;13(6):425-31
references: 12468243
references: Shock. 2005 May;23(5):453-8
references: 15834312
references: Am J Pathol. 1998 Jun;152(6):1577-89
references: 9626061
references: Nature. 1994 Jul 21;370(6486):218-20
references: 8028669
references: J Immunol. 2007 Sep 1;179(5):2686-9
references: 17709479
references: Liver. 2000 Feb;20(1):66-77
references: 10726963
references: Liver Int. 2006 Dec;26(10):1175-86
references: 17105582
references: Proc Soc Exp Biol Med. 1959 Oct-Dec;102:672-5
references: 14415256
references: Am J Pathol. 2010 Jun;176(6):2669-81
references: 20395437
references: Hepatology. 2006 Feb;43(2 Suppl 1):S45-53
references: 16447274
references: J Immunol. 2006 Jan 15;176(2):721-5
references: 16393953
references: Gastroenterology. 2005 Feb;128(2):424-32
references: 15685553
references: World J Gastroenterol. 2008 Mar 7;14(9):1353-7
references: 18322947
references: Hepatology. 1986 Sep-Oct;6(5):830-6
references: 3758936
references: J Biol Chem. 2002 Apr 12;277(15):12838-45
references: 11823465
references: FEBS Lett. 1998 Sep 11;435(1):39-44
references: 9755855
references: Genesis. 2000 Feb;26(2):149-50
references: 10686614
references: PLoS One. 2010 Sep 16;5(9):
references: 20862286
references: Science. 1995 Sep 8;269(5229):1427-9
references: 7660125
references: J Biol Chem. 2001 Jul 13;276(28):26605-13
references: 11349125
references: J Cell Biol. 2004 Mar 1;164(5):769-79
references: 14993236
references: Mech Dev. 2013 Apr-May;130(4-5):272-89
references: 23354118
references: Toxicol Lett. 2001 Mar 31;120(1-3):317-21
references: 11323190
references: Science. 1998 Nov 13;282(5392):1281-4
references: 9812885
references: Cell Biol Int. 2001;25(7):585-92
references: 11448096
references: J Clin Invest. 2010 Aug;120(8):2731-44
references: 20628198
references: J Biol Chem. 2004 Aug 13;279(33):34530-6
references: 15199050
references: Transgenic Res. 1999 Aug;8(4):265-77
references: 10621974
references: Hepatology. 1998 Nov;28(5):1226-34
references: 9794905
references: Nat Genet. 2004 Sep;36(9):969-77
references: 15322543
references: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17081-6
references: 17940036
references: J Clin Invest. 2002 Jul;110(2):193-202
references: 12122111
references: J Exp Med. 2004 Aug 2;200(3):367-76
references: 15289505