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