Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway.

Treatment of mice with lipopolysaccharide (LPS) and the liver-specific transcriptional inhibitor D-(+)-galactosamine (GalN) induces fatal hepatitis, which is mediated by tumor necrosis factor α (TNF-α) and characterized by massive hepatic apoptosis. Previous studies suggest that GalN increases the sensitivity to LPS/TNF-α, probably by blocking the transcription of protective factors, but the identity of most of these factors is still unclear. Here, we report that Ifit1 protects against LPS/GalN-induced fatal hepatitis. Forced expression of Ifit1 in hepatocytes significantly diminished TNF-α-mediated apoptosis. Moreover, targeted expression of Ifit1 in the liver by recombinant adeno-associated virus serotype 8 protected mice from LPS/GalN-induced lethal hepatitis, which was associated with the inhibition of TNF-α-mediated activation of the c-Jun N-terminal kinase (JNK)-Bim cascade. Furthermore, Ifit1 bound to a scaffolding protein Axin and inhibited its function to mediate JNK activation. Together, our data demonstrate that Ifit1 is a novel protective factor that inhibits LPS/GalN-induced (TNF-α-mediated) fatal hepatitis, suggesting that Ifit1 is a potential therapeutic target for treatment of inflammatory liver diseases.

[1]  Giulio Superti-Furga,et al.  Structural basis for viral 5′-PPP-RNA recognition by human IFIT proteins , 2013, Nature.

[2]  Lili Wang.  Adeno‐associated virus gene therapy prevents hepatocellular adenoma in murine model of glycogen storage disease type Ia , 2012, Hepatology.

[3]  Pratima Chowdary,et al.  Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. , 2011, The New England journal of medicine.

[4]  M. Kay,et al.  Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo , 2010, Hepatology.

[5]  J. Chambard,et al.  ERK and cell death: Mechanisms of ERK‐induced cell death – apoptosis, autophagy and senescence , 2010, The FEBS journal.

[6]  A. Strasser,et al.  Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim. , 2009, Immunity.

[7]  G. Sen,et al.  Interferon‐inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1 , 2008, The EMBO journal.

[8]  Hemant Ishwaran,et al.  An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer , 2008, Proceedings of the National Academy of Sciences.

[9]  H. Hsu,et al.  TNF-alpha mediates pseudorabies virus-induced apoptosis via the activation of p38 MAPK and JNK/SAPK signaling. , 2008, Virology.

[10]  M. Menger,et al.  Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure , 2008, Apoptosis.

[11]  G. Johnson,et al.  MEKK4 Stimulation of p38 and JNK Activity Is Negatively Regulated by GSK3β* , 2007, Journal of Biological Chemistry.

[12]  Feng Liu,et al.  Metabolic profiling analysis of a D-galactosamine/lipopolysaccharide-induced mouse model of fulminant hepatic failure. , 2007, Journal of proteome research.

[13]  S. Monga,et al.  WNT/β‐catenin signaling in liver health and disease , 2007 .

[14]  Kenji Suzuki,et al.  An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. , 2007, Life sciences.

[15]  Jiahuai Han,et al.  Differential requirement of MKK4 and MKK7 in JNK activation by distinct scaffold proteins , 2007, FEBS letters.

[16]  W. Merrick,et al.  Distinct Induction Patterns and Functions of Two Closely Related Interferon-inducible Human Genes, ISG54 and ISG56* , 2006, Journal of Biological Chemistry.

[17]  M. Ricote,et al.  P38 MAPK protects against TNF-α-provoked apoptosis in LNCaP prostatic cancer cells , 2006, Apoptosis.

[18]  C. Libert,et al.  Adenoviral gene transfer of ABIN‐1 protects mice from TNF/galactosamine‐induced acute liver failure and lethality , 2005, Hepatology.

[19]  T. Kuwana,et al.  BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. , 2005, Molecular cell.

[20]  Xiao-Ming Yin,et al.  Dissection of the multiple mechanisms of TNF‐α‐induced apoptosis in liver injury , 2004 .

[21]  T. Andersson,et al.  p38 MAPK mediates TNF-induced apoptosis in endothelial cells via phosphorylation and downregulation of Bcl-x(L). , 2004, Experimental cell research.

[22]  M. Tsuchiya,et al.  Evaluation of the bacterial endotoxin test for quantification of endotoxin contamination of porcine vaccines. , 2004, Biologicals : journal of the International Association of Biological Standardization.

[23]  Jiahuai Han,et al.  Axin Utilizes Distinct Regions for Competitive MEKK1 and MEKK4 Binding and JNK Activation* , 2003, Journal of Biological Chemistry.

[24]  Eugene M. Johnson,et al.  JNK-Mediated BIM Phosphorylation Potentiates BAX-Dependent Apoptosis , 2003, Neuron.

[25]  K. Lei,et al.  JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  N. Raab-Traub,et al.  I-mfa Domain Proteins Interact with Axin and Affect Its Regulation of the Wnt and c-Jun N-Terminal Kinase Signaling Pathways , 2002, Molecular and Cellular Biology.

[27]  Y. Yoo,et al.  Role of p38 MAPK in the regulation of apoptosis signaling induced by TNF-alpha in differentiated PC12 cells. , 2002, Journal of biochemistry and molecular biology.

[28]  C. Ferran,et al.  A20 protects mice from D‐galactosamine/lipopolysaccharide acute toxic lethal hepatitis , 2002, Hepatology.

[29]  T Takahashi,et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis , 2001, EMBO reports.

[30]  N. Holbrook,et al.  Requirement for ERK Activation in Cisplatin-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[31]  A. Strasser,et al.  BH3-Only Proteins—Essential Initiators of Apoptotic Cell Death , 2000, Cell.

[32]  S. Neo,et al.  Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels. , 2000, Biochemical and biophysical research communications.

[33]  Jiahuai Han,et al.  Axin Forms a Complex with MEKK1 and Activates c-Jun NH2-terminal Kinase/Stress-activated Protein Kinase through Domains Distinct from Wnt Signaling* , 1999, The Journal of Biological Chemistry.

[34]  A. Strasser,et al.  The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. , 1999, Molecular cell.

[35]  Minoru Takagi,et al.  Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways , 1997, Science.