Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation
Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation
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DOI：
10.1189/jlb.0905505
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发表时间：
2006-04-01
影响因子：
5.5
通讯作者：
Redmond, H. Paul
中科院分区：
文献类型：
--
作者：
Li, Chong Hui;Wang, Jiang Huai;Redmond, H. Paul
对细菌细胞壁成分的耐受性可能是细菌感染过程中必不可少的调节机制。我们之前已经证明，核因子(NF)- κ B和丝裂原活化的蛋白激酶活化存在于细菌脂蛋白（BLP）自身耐受性及其对脂多糖（LPS）的交叉耐受性中。在本研究中，我们进一步研究了blp诱导的耐受对体外NF-kappa B激活的髓样分化因子88 （MyD88）依赖的上游信号通路的影响。与不耐受的人单核THP-1细胞相比，BLP耐受细胞在高剂量BLP （86 +/- 12 vs. 6042 +/- 245 mg/ml, P < 0.01）或LPS （341 +/- 36 vs. 7882 +/- 318 mg/ml, P < 0.01）刺激下，肿瘤坏死因子et （tnf - α）的产生显著减少。toll样受体2 （TLR2）蛋白在blp耐受细胞中表达下调，而TLR4、MyD88、白细胞介素-1受体相关激酶4 （IRAK-4）和TNF受体相关因子6的表达在blp不耐受细胞和blp耐受细胞中无显著差异，Western blot分析证实。实时逆转录-聚合酶链式反应分析显示，IRAK-1蛋白在blp耐受细胞中显著降低，但IRAK-1 mRNA的表达保持不变。此外，免疫沉淀表明，在第二次BLP或LPS刺激后，在BLP耐受细胞中观察到MyD88-IRAK免疫复合物形成减少。BLP预处理还导致kappa b - α总和磷酸化抑制剂（I kappa b - α）的表达明显抑制，随后的BLP或LPS刺激没有上调。这些结果表明，除了TLR2表达下调外，BLP耐受性还与IRAK-1表达降低、MyD88-IRAK关联以及I κ pa b - α磷酸化有关。这些发现进一步阐明了细菌肽耐受的分子机制。j . Leukoc。中国生物医学工程学报（英文版）；2006。
Tolerance to bacterial cell-wall components may represent an essential regulatory mechanism during bacterial infection. We have demonstrated previously that the inhibition of nuclear factor (NF)-kappa B and mitogen-activated protein kinase activation was present in bacterial lipoprotein (BLP) self-tolerance and its cross-tolerance to lipopolysaccharide (LPS). In this study, the effect of BLP-induced tolerance on the myeloid differentiation factor 88 (MyD88)-dependent upstream signaling pathway for NF-kappa B activation in vitro was examined further. When compared with nontolerant human monocytic THP-1 cells, BLP-tolerant cells had a significant reduction in tumor necrosis factor et (TNF-alpha) production in response to a high-dose BLP (86 +/- 12 vs. 6042 +/- 245 mg/ml, P < 0.01) or LPS (341 +/- 36 vs. 7882 +/- 318 mg/ml, P < 0.01) stimulation. The expression of Toll-like receptor 2 (TLR2) protein was down-regulated in BLP-tolerant cells, whereas no significant differences in TLR4, MyD88, interleukin-1 receptor-associated kinase 4 (IRAK-4), and TNF receptor-associated factor 6 expression were observed between nontolerant and BLP-tolerant cells, as confirmed by Western blot analysis. The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis. Furthermore, decreased MyD88-IRAK immunocomplex formation, as demonstrated by immunoprecipitation, was observed in BLP-tolerant cells following a second BLP or LPS stimulation. BLP pretreatment also resulted in a marked inhibition in total and phosphorylated inhibitor Of kappa B-alpha (I kappa B-alpha) expression, which was not up-regulated by subsequent BLP or LPS stimulation. These results demonstrate that in addition to the down-regulation of TLR2 expression, BLP tolerance is associated with a reduction in IRAK-1 expression, MyD88-IRAK association, and I kappa B-alpha phosphorylation. These findings further elucidate the molecular mechanisms underlying bacterial peptide tolerance. J. Leukoc. Biol. 79: 867-875;2006.