CpG DNA-mediated induction of acute liver injury in D-Galactosamine- sensitized mice

The mitochondrial apoptotic pathway-dependent death of hepatocytes

Ae-Kyung Yi, Hyunsook Yoon, Jeoung Eun Park, Beom Sue Kim, Hae Jong Kim, Antonio Martinez-Hernandez

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce innate inflammatory responses, including rapid induction of proinflammatory cytokines. Although innate inflammatory responses induced by CpG DNA and other pathogen-associated molecular patterns are essential for the eradication of infectious microorganisms, excessive activation of innate immunity is detrimental to the host. In this study, we demonstrate that CpG DNA, but not control non-CpG DNA, induces a fulminant liver failure with subsequent shock-mediated death by promoting massive apoptotic death of hepatocytes in D-galactosamine (D-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activity in vivo protects D-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines in D-GalN-sensitized mice via a TLR9/MyD88-dependent pathway. In addition, CpG DNA failed to induce massive hepatocyte apoptosis and subsequent fulminant liver failure and death in D-GalN-sensitized mice that lack TLR9, MyD88, tumor necrosis factor (TNF)-α, or TNF receptor I but not interleukin-6 or -12p40. Taken together, our results provide direct evidence that CpG DNA induces a severe acute liver injury and shock-mediated death through the mitochondrial apoptotic pathway-dependent death of hepatocytes caused by an enhanced production of TNF-α through a TLR9/MyD88 signaling pathway in D-GalN-sensitized mice.

Original languageEnglish (US)
Pages (from-to)15001-15012
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number21
DOIs
StatePublished - May 26 2006

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Galactosamine
Liver
Hepatocytes
DNA
Wounds and Injuries
Acute Liver Failure
Shock
Tumor Necrosis Factor-alpha
Cytokines
Bacterial DNA
Caspase 9
Tumor Necrosis Factor Receptors
Mitochondrial Membranes
Innate Immunity
Microorganisms
Interleukin-6
Chemical activation
Apoptosis
Membranes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

CpG DNA-mediated induction of acute liver injury in D-Galactosamine- sensitized mice : The mitochondrial apoptotic pathway-dependent death of hepatocytes. / Yi, Ae-Kyung; Yoon, Hyunsook; Park, Jeoung Eun; Kim, Beom Sue; Kim, Hae Jong; Martinez-Hernandez, Antonio.

In: Journal of Biological Chemistry, Vol. 281, No. 21, 26.05.2006, p. 15001-15012.

Research output: Contribution to journalArticle

Yi, Ae-Kyung ; Yoon, Hyunsook ; Park, Jeoung Eun ; Kim, Beom Sue ; Kim, Hae Jong ; Martinez-Hernandez, Antonio. / CpG DNA-mediated induction of acute liver injury in D-Galactosamine- sensitized mice : The mitochondrial apoptotic pathway-dependent death of hepatocytes. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 21. pp. 15001-15012.
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abstract = "Unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce innate inflammatory responses, including rapid induction of proinflammatory cytokines. Although innate inflammatory responses induced by CpG DNA and other pathogen-associated molecular patterns are essential for the eradication of infectious microorganisms, excessive activation of innate immunity is detrimental to the host. In this study, we demonstrate that CpG DNA, but not control non-CpG DNA, induces a fulminant liver failure with subsequent shock-mediated death by promoting massive apoptotic death of hepatocytes in D-galactosamine (D-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activity in vivo protects D-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines in D-GalN-sensitized mice via a TLR9/MyD88-dependent pathway. In addition, CpG DNA failed to induce massive hepatocyte apoptosis and subsequent fulminant liver failure and death in D-GalN-sensitized mice that lack TLR9, MyD88, tumor necrosis factor (TNF)-α, or TNF receptor I but not interleukin-6 or -12p40. Taken together, our results provide direct evidence that CpG DNA induces a severe acute liver injury and shock-mediated death through the mitochondrial apoptotic pathway-dependent death of hepatocytes caused by an enhanced production of TNF-α through a TLR9/MyD88 signaling pathway in D-GalN-sensitized mice.",
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