Kim Young-In, Park Jeoung-Eun, Martinez-Hernandez Antonio, Yi Ae-Kyung
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.
J Biol Chem. 2008 May 30;283(22):15258-70. doi: 10.1074/jbc.M709549200. Epub 2008 Mar 31.
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.
巨噬细胞响应CpG DNA产生的肿瘤坏死因子-α（TNF-α）可诱导严重肝损伤，并导致D-半乳糖胺（D-GalN）致敏小鼠死亡。在本研究中，我们证明预先接触CpG DNA的小鼠对CpG DNA/D-GalN诱导的肝损伤和死亡具有抗性。CpG DNA/D-GalN未能在预先接触CpG DNA的小鼠中诱导TNF-α产生和肝细胞凋亡。此外，从经CpG DNA预处理的小鼠中分离出的巨噬细胞对CpG DNA的反应显示出丝裂原活化蛋白激酶（MAPKs）和核因子κB（NF-κB）的激活受到抑制以及TNF-α产生减少，这表明CpG DNA介导的对CpG DNA/D-GalN攻击小鼠的保护作用是由于巨噬细胞对CpG DNA反应性降低。体内CpG DNA预处理抑制了巨噬细胞中白细胞介素-1受体相关激酶（IRAK）-1的表达，同时诱导了IRAK-M的表达。IRAK-1表达的抑制导致巨噬细胞对CpG DNA反应性降低。然而，IRAK-M表达的增加不足以使巨噬细胞对CpG DNA反应性降低，但却是诱导巨噬细胞最佳反应性水平所必需的。综上所述，CpG DNA预处理后IRAK-1表达降低和IRAK-M表达增加导致巨噬细胞反应性降低，从而保护小鼠免受CpG DNA/D-GalN引起的肝损伤和死亡。
