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PMID: 19167327 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Induction of hepatitis by JNK-mediated expression of TNF-alpha.

Cell ·Vol. 136 ·No. 2 ·2009-01-23 ·Pages 249-60

Das M, Sabio G, Jiang F, Rincón M, Flavell RA, Davis RJ

Abstract

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway has been implicated in the development of tumor necrosis factor (TNF)-dependent hepatitis. JNK may play a critical role in hepatocytes during TNF-stimulated cell death in vivo. To test this hypothesis, we examined the phenotype of mice with compound disruption of the Jnk1 and Jnk2 genes. Mice with loss of JNK1/2 expression in hepatocytes exhibited no defects in the development of hepatitis compared with control mice, whereas mice with loss of JNK1/2 in the hematopoietic compartment exhibited a profound defect in hepatitis that was associated with markedly reduced expression of TNF-alpha. These data indicate that JNK is required for TNF-alpha expression but not for TNF-alpha-stimulated death of hepatocytes. Indeed, TNF-alpha induced similar hepatic damage in both mice with hepatocyte-specific JNK1/2 deficiency and control mice. These observations confirm a role for JNK in the development of hepatitis but identify hematopoietic cells as the site of the essential function of JNK.

MeSH Terms
Animals Hepatitis/metabolism Hepatocytes/metabolism Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinase 8/genetics,metabolism Mitogen-Activated Protein Kinase 9/genetics,metabolism Tumor Necrosis Factor-alpha/metabolism
Chemicals
Tumor Necrosis Factor-alpha Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinase 8
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Das Madhumita
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sabio Guadalupe
Jiang Feng
Rincón Mercedes
Flavell Richard A
Davis Roger J
References (69)
69 references, click to expand
  1. JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways.
    Cell Death Differ. 2004 Mar;11(3):301-13 PMID: 14685158
  2. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene.
    Nature. 2003 Jan 30;421(6922):547-51 PMID: 12540851
  3. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death.
    Cell. 1996 Nov 1;87(3):565-76 PMID: 8898208
  4. Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis.
    Oncogene. 2002 Apr 4;21(15):2441-5 PMID: 11948429
  5. Tumor necrosis factor: an apoptosis JuNKie?
    Cell. 2004 Feb 20;116(4):491-7 PMID: 14980217
  6. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines.
    Genes Dev. 2001 Jun 1;15(11):1419-26 PMID: 11390361
  7. Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway.
    J Biol Chem. 2006 Jun 2;281(22):15258-67 PMID: 16571730
  8. A T cell-dependent experimental liver injury in mice inducible by concanavalin A.
    J Clin Invest. 1992 Jul;90(1):196-203 PMID: 1634608
  9. Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2.
    Immunity. 1998 Oct;9(4):575-85 PMID: 9806643
  10. JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species.
    Genes Dev. 2004 Dec 1;18(23):2905-15 PMID: 15545623
  11. Defective T cell differentiation in the absence of Jnk1.
    Science. 1998 Dec 11;282(5396):2092-5 PMID: 9851932
  12. Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo.
    Mol Cell Biol. 2005 Apr;25(8):3348-56 PMID: 15798218
  13. The roles of innate immune cells in liver injury and regeneration.
    Cell Mol Immunol. 2007 Aug;4(4):241-52 PMID: 17764614
  14. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.
    Genes Dev. 2005 Nov 15;19(22):2668-81 PMID: 16260493
  15. Inhibition of JNK activation through NF-kappaB target genes.
    Nature. 2001 Nov 15;414(6861):313-7 PMID: 11713531
  16. Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis.
    Eur J Immunol. 1998 Dec;28(12):4105-13 PMID: 9862346
  17. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis.
    Mol Cell Biol. 2004 Dec;24(24):10844-56 PMID: 15572687
  18. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.
    J Exp Med. 2000 Jan 3;191(1):105-14 PMID: 10620609
  19. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
    Immunity. 2007 Oct;27(4):647-59 PMID: 17919941
  20. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development.
    Neuron. 1999 Apr;22(4):667-76 PMID: 10230788
  21. A JNK-dependent pathway is required for TNFalpha-induced apoptosis.
    Cell. 2003 Oct 3;115(1):61-70 PMID: 14532003
  22. JunD mediates survival signaling by the JNK signal transduction pathway.
    Mol Cell. 2003 Jun;11(6):1479-89 PMID: 12820962
  23. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway.
    Cell. 2000 Dec 22;103(7):1071-83 PMID: 11163183
  24. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice.
    Gastroenterology. 2002 Jun;122(7):2001-10 PMID: 12055605
  25. Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A.
    Gastroenterology. 1996 Aug;111(2):462-71 PMID: 8690213
  26. A novel accessory role of neutrophils in concanavalin A-induced hepatitis.
    Cell Immunol. 2005 Jan;233(1):23-9 PMID: 15893298
  27. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway.
    Science. 2000 May 5;288(5467):870-4 PMID: 10797012
  28. In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis.
    Eur J Immunol. 1997 Nov;27(11):2870-5 PMID: 9394812
  29. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.
    J Biol Chem. 1999 Jan 1;274(1):305-15 PMID: 9867845
  30. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2.
    Nature. 2002 Mar 21;416(6878):345-7 PMID: 11907583
  31. c-Jun NH(2)-terminal kinase is essential for the regulation of AP-1 by tumor necrosis factor.
    Mol Cell Biol. 2003 Apr;23(8):2871-82 PMID: 12665585
  32. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death.
    EMBO J. 2003 Aug 1;22(15):3898-909 PMID: 12881424
  33. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element.
    Mol Cell Biol. 2006 Mar;26(6):2399-407 PMID: 16508014
  34. Ubiquitin-mediated activation of TAK1 and IKK.
    Oncogene. 2007 May 14;26(22):3214-26 PMID: 17496917
  35. Suppression of p53-dependent senescence by the JNK signal transduction pathway.
    Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15759-64 PMID: 17893331
  36. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway.
    Science. 1997 Jan 10;275(5297):200-3 PMID: 8985011
  37. TNF-R1 signaling: a beautiful pathway.
    Science. 2002 May 31;296(5573):1634-5 PMID: 12040173
  38. Essential function for the kinase TAK1 in innate and adaptive immune responses.
    Nat Immunol. 2005 Nov;6(11):1087-95 PMID: 16186825
  39. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor.
    Cell. 1995 Dec 1;83(5):793-802 PMID: 8521496
  40. Jun kinase modulates tumor necrosis factor-dependent apoptosis in liver cells.
    Hepatology. 2002 Aug;36(2):315-25 PMID: 12143039
  41. Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation.
    J Biol Chem. 2003 Oct 24;278(43):42307-12 PMID: 12907675
  42. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8.
    J Cell Sci. 2002 Jul 1;115(Pt 13):2757-70 PMID: 12077366
  43. The p65/RelA subunit of NF-kappaB suppresses the sustained, antiapoptotic activity of Jun kinase induced by tumor necrosis factor.
    Mol Cell Biol. 2002 Dec;22(23):8175-83 PMID: 12417721
  44. TNF-alpha induces two distinct caspase-8 activation pathways.
    Cell. 2008 May 16;133(4):693-703 PMID: 18485876
  45. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin.
    Blood. 1995 Dec 1;86(11):4184-93 PMID: 7492776
  46. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species.
    Cell. 2004 Nov 12;119(4):529-42 PMID: 15537542
  47. Inducible gene targeting in mice.
    Science. 1995 Sep 8;269(5229):1427-9 PMID: 7660125
  48. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.
    Cell. 2003 Jul 25;114(2):181-90 PMID: 12887920
  49. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
    J Immunol. 2003 Sep 15;171(6):3233-44 PMID: 12960353
  50. Regulation of lymphocyte proliferation and death by FLIP.
    Nat Rev Immunol. 2001 Oct;1(1):50-8 PMID: 11905814
  51. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis.
    EMBO Rep. 2001 Mar;2(3):222-8 PMID: 11266364
  52. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.
    Nature. 2001 Nov 15;414(6861):308-13 PMID: 11713530
  53. Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis.
    J Immunol. 2004 Jan 1;172(1):45-53 PMID: 14688308
  54. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.
    Cell. 2005 Mar 11;120(5):649-61 PMID: 15766528
  55. Chemical genetic analysis of the time course of signal transduction by JNK.
    Mol Cell. 2006 Mar 3;21(5):701-10 PMID: 16507367
  56. JNK2 is a positive regulator of the cJun transcription factor.
    Mol Cell. 2006 Sep 15;23(6):899-911 PMID: 16973441
  57. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha.
    Immunity. 2003 Nov;19(5):725-37 PMID: 14614859
  58. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover.
    Cell. 2006 Feb 10;124(3):601-13 PMID: 16469705
  59. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.
    Nature. 1996 Mar 7;380(6569):75-9 PMID: 8598911
  60. TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination.
    EMBO J. 2005 May 18;24(10):1886-98 PMID: 15861135
  61. Targeting JNK for therapeutic benefit: from junk to gold?
    Nat Rev Drug Discov. 2003 Jul;2(7):554-65 PMID: 12815381
  62. The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor.
    Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):570-5 PMID: 9435233
  63. A crucial role for p80 TNF-R2 in amplifying p60 TNF-R1 apoptosis signals in T lymphocytes.
    Eur J Immunol. 2000 Feb;30(2):652-60 PMID: 10671223
  64. Signal transduction by the JNK group of MAP kinases.
    Cell. 2000 Oct 13;103(2):239-52 PMID: 11057897
  65. Critical contribution of liver natural killer T cells to a murine model of hepatitis.
    Proc Natl Acad Sci U S A. 2000 May 9;97(10):5498-503 PMID: 10792025
  66. Activated Kupffer cells play an important role in intra-hepatic Th1-associated necro-inflammation in Concanavalin A-induced hepatic injury in mice.
    Hepatol Res. 2003 Oct;27(2):143-150 PMID: 14563429
  67. Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level.
    J Exp Med. 1990 Feb 1;171(2):465-75 PMID: 2303781
  68. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death.
    Mol Cell. 2007 Jun 8;26(5):675-87 PMID: 17560373
  69. A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo.
    Mol Cell Biol. 2000 Aug;20(16):6084-94 PMID: 10913190
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2008.11.017
Published
2009-01-23
Pages
249-60
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2794880
Subset
IM
Grants
NCI NIH HHS · R01 CA065861-14 · United States
NCI NIH HHS · R01 CA065861 · United States
NIDDK NIH HHS · P30 DK032520-26 · United States
Howard Hughes Medical Institute · United States
NIDDK NIH HHS · P30 DK032520 · United States
NIDDK NIH HHS · P30 DK 32520 · United States
NIAID NIH HHS · R01 AI051454 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2008.11.017 PMC Full Text View journal details
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