Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells
Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells
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DOI：
10.1093/intimm/dxq062
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发表时间：
2010-09-01
影响因子：
4.4
通讯作者：
Izuhara, Kenji
中科院分区：
文献类型：
--
作者：
Matsushita, Hidetomo;Ohta, Shoichiro;Izuhara, Kenji
树突状细胞（dc）和单核/巨噬细胞先前暴露于LPS会导致对随后的LPS刺激无反应，这种现象称为内毒素耐受（ET）。ET通过下调MHC II类和共刺激分子如CD86和CD40的表达，损害这些细胞向T细胞的抗原呈递。一些流行病学研究表明，内毒素是过敏性疾病的保护因素。因此，LPS通过T(h)1偏斜或诱导调节性T细胞，对模型动物气道变应性炎症的发生具有有益作用。然而，来自哮喘模型动物的结果是有争议的，可能是由于处理LPS的困难。我们之前生成了一种针对toll样受体（TLR） 4的单克隆激动抗体，命名为UT12，它模仿LPS的生物活性，表现出比LPS更有效和持续的ET。在本研究中，我们利用UT12产生延长的ET，探讨ET参与TLR4信号对哮喘模型小鼠抑制作用的可能性。UT12诱导ET抑制DCs扩增卵白蛋白（OVA）特异性T(h)2和T(h)17细胞的能力，而不诱导T(h)1细胞或调节性T细胞群或产生抑制性细胞因子。因此，在致敏前给药UT12可显著抑制吸入OVA引起的气道变应性炎症。综上所述，这些结果表明，在哮喘模型小鼠中，激活TLR4信号诱导的ET通过直接抑制dc的t细胞刺激作用来减轻气道变应性炎症。
Prior exposure of dendritic cells (DCs) and monocytes/macrophages to LPS causes unresponsiveness to subsequent LPS stimulation, a phenomenon called endotoxin tolerance (ET). ET impairs antigen presentation of these cells to T cells by down-regulating expression of MHC class II and co-stimulatory molecules such as CD86 and CD40. Some epidemiological studies have shown that endotoxin acts as a protective factor for allergic diseases. Accordingly, LPS has beneficial effects on the onset of airway allergic inflammation in model animals by T(h)1 skewing or induction of regulatory T cells. However, results derived from asthma model animals are controversial, probably due to the difficulty of handling LPS. We previously generated a monoclonal agonistic antibody against Toll-like receptor (TLR) 4, named UT12, which mimics the biological activities of LPS, exhibiting more potent and sustained ET than does LPS. In this study, we took advantage of UT12 to generate prolonged ET to explore the possibility that ET is involved in the inhibitory effects of the TLR4 signals on asthma model mice. Induction of ET by UT12 inhibited the capacity of DCs to expand ovalbumin (OVA)-specific T(h)2 and T(h)17 cells, without inducing T(h)1 cell or regulatory T-cell populations or producing inhibitory cytokines. Accordingly, administration of UT12 before the OVA sensitization significantly suppressed airway allergic inflammation by OVA inhalation. Taken together, these results demonstrate that ET induced by activating TLR4 signals attenuates airway allergic inflammation through direct suppression of the T-cell stimulatory effect of DCs in asthma model mice.