CpG DNA prevents liver injury and shock-mediated death by modulating expression of interleukin-1 receptor-associated kinases

Young In Kim Hoehamer, Jeoung Eun Park, Antonio Martinez-Hernandez, Ae-Kyung Yi

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNF-α) produced by macrophages in response to CpG DNA induces severe liver injury and subsequent death of D-galactosamine (D-GalN)-sensitized mice. In the present study we demonstrate that mice pre-exposed to CpG DNA are resistant to liver injury and death induced by CpG DNA/D-GalN. CpG DNA/D-GalN failed to induce TNF-α production and hepatocyte apoptosis in the mice pre-exposed to CpG DNA. In addition, macrophages isolated from the CpG DNA-pretreated mice showed suppressed activation of MAPKs and NF-κB and production of TNF-α in response to CpG DNA, indicating that the CpG DNA-mediated protection of CpG DNA/D-GalN-challenged mice is due to the hyporesponsiveness of macrophages to CpG DNA. CpG DNA pretreatment in vivo inhibited expression of interleukin-1 receptor-associated kinase (IRAK)-1 while inducing IRAK-M expression in macrophages. Suppressed expression of IRAK-1 was responsible for the macrophage hyporesponsiveness to CpG DNA. However, increased expression of IRAK-M was not sufficient to render macrophages hyporesponsive to CpG DNA but was required for induction of the optimal level of macrophage hyporesponsiveness. Taken together, reduced expression of IRAK-1 and increased expression of IRAK-M after CpG DNA pretreatment resulted in the hyporesponsiveness of macrophages that leads to the protection of mice from hepatic injury and death caused by CpG DNA/D-GalN.

Original languageEnglish (US)
Pages (from-to)15258-15270
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number22
DOIs
StatePublished - May 30 2008

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Interleukin-1 Receptor-Associated Kinases
Liver
Shock
Macrophages
DNA
Wounds and Injuries
Galactosamine
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

CpG DNA prevents liver injury and shock-mediated death by modulating expression of interleukin-1 receptor-associated kinases. / Kim Hoehamer, Young In; Park, Jeoung Eun; Martinez-Hernandez, Antonio; Yi, Ae-Kyung.

In: Journal of Biological Chemistry, Vol. 283, No. 22, 30.05.2008, p. 15258-15270.

Research output: Contribution to journalArticle

Kim Hoehamer, Young In ; Park, Jeoung Eun ; Martinez-Hernandez, Antonio ; Yi, Ae-Kyung. / CpG DNA prevents liver injury and shock-mediated death by modulating expression of interleukin-1 receptor-associated kinases. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 22. pp. 15258-15270.
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abstract = "Tumor necrosis factor-α (TNF-α) produced by macrophages in response to CpG DNA induces severe liver injury and subsequent death of D-galactosamine (D-GalN)-sensitized mice. In the present study we demonstrate that mice pre-exposed to CpG DNA are resistant to liver injury and death induced by CpG DNA/D-GalN. CpG DNA/D-GalN failed to induce TNF-α production and hepatocyte apoptosis in the mice pre-exposed to CpG DNA. In addition, macrophages isolated from the CpG DNA-pretreated mice showed suppressed activation of MAPKs and NF-κB and production of TNF-α in response to CpG DNA, indicating that the CpG DNA-mediated protection of CpG DNA/D-GalN-challenged mice is due to the hyporesponsiveness of macrophages to CpG DNA. CpG DNA pretreatment in vivo inhibited expression of interleukin-1 receptor-associated kinase (IRAK)-1 while inducing IRAK-M expression in macrophages. Suppressed expression of IRAK-1 was responsible for the macrophage hyporesponsiveness to CpG DNA. However, increased expression of IRAK-M was not sufficient to render macrophages hyporesponsive to CpG DNA but was required for induction of the optimal level of macrophage hyporesponsiveness. Taken together, reduced expression of IRAK-1 and increased expression of IRAK-M after CpG DNA pretreatment resulted in the hyporesponsiveness of macrophages that leads to the protection of mice from hepatic injury and death caused by CpG DNA/D-GalN.",
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