title: CpG DNA prevents liver injury and shock-mediated death by modulating expression of interleukin-1 receptor-associated kinases.
abstract: Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-kappaB and production of TNF-alpha 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.
authors: The Children's Foundation Research Center at Le Bonheur Children's Medical Center, and Department of Pediatrics, University of Tennessee Health Science Center, 50 N. Dunlap Street, Memphis, TN 38103, USA.
authors: Young-In
authors: YI
authors: Kim
authors: Jeoung-Eun
authors: JE
authors: Park
authors: Antonio
authors: A
authors: Martinez-Hernandez
authors: Ae-Kyung
authors: AK
authors: Yi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005688:Galactosamine / Q000819:agonists / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis*; D008099:Liver / Q000201:enzymology* / Q000293:injuries; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000819:agonists / Q000633:toxicity*; D012769:Shock / Q000139:chemically induced / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507772:Irak3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases