van 't Veer Cornelis, van den Pangaart Petra S, van Zoelen Marieke A D, de Kruif Martijn, Birjmohun Rakesh S, Stroes Eric S, de Vos Alex F, van der Poll Tom
Center for Infection and Immunity Amsterdam, The Netherland.
J Immunol. 2007 Nov 15;179(10):7110-20. doi: 10.4049/jimmunol.179.10.7110.
Recent in vitro and murine in vivo studies have identified several potential LPS tolerance factors. In this study, we describe the expression kinetics of these LPS tolerance factors in standardized human endotoxemia models using i.v. LPS bolus administration. Responsiveness to LPS as well as the expression of potential regulators of LPS signaling were determined in peripheral whole blood. Intravenous LPS administration (4 ng/kg) resulted in peak plasma levels of TNF-alpha at 1.5 h followed by subsequent peaks of the classic negative feedback inhibitors A20 and IL-10 at 2 and 3 h, respectively. Circulating blood monocyte counts decimated during the initial inflammatory response, but normalized in the period between 4 and 8 h post-LPS. The LPS response as determined by ex vivo TNF release per monocyte in whole blood was profoundly decreased at 6-8 h post-LPS injection despite cessation of A20 and IL-10 expression after 4 h. Analysis of MyD88short, IL-1R-associated kinase (IRAK)-1, IRAK-M, ST2, suppressor of cytokine signaling-1 and -3, SHIP-1, and MAP kinase phosphatase-1 expression indicated that the observed LPS tolerance was associated with decreased IRAK-1 and elevated IRAK-M expression in this human model. Interestingly, a lower dose of LPS (1 ng/kg) induced LPS tolerance accompanied with IRAK-M up-regulation but without depletion of IRAK-1. In vitro studies in whole blood showed that IRAK-M up-regulation by LPS is largely dependent on TNF-alpha. The observed rise of IRAK-M transcription in the human endotoxemia model appeared much greater compared with in vitro-stimulated whole blood. In conclusion, LPS tolerance in human endotoxemia models is associated with IRAK-M up-regulation.
最近的体外和小鼠体内研究已经确定了几种潜在的脂多糖（LPS）耐受因子。在本研究中，我们描述了这些LPS耐受因子在使用静脉推注LPS的标准化人类内毒素血症模型中的表达动力学。在全外周血中测定了对LPS的反应性以及LPS信号传导潜在调节因子的表达。静脉注射LPS（4 ng/kg）导致肿瘤坏死因子-α（TNF-α）的血浆峰值水平在1.5小时出现，随后经典负反馈抑制剂A20和白细胞介素-10（IL-10）的峰值分别在2小时和3小时出现。循环血单核细胞计数在初始炎症反应期间减少，但在LPS注射后4至8小时恢复正常。尽管在4小时后A20和IL-10表达停止，但在LPS注射后6至8小时，通过全血中每个单核细胞的体外TNF释放测定的LPS反应性显著降低。对髓样分化因子88（MyD88）短型、白细胞介素-1受体相关激酶（IRAK）-1、IRAK-M、ST2、细胞因子信号传导抑制因子-1和-3、SHIP-1以及丝裂原活化蛋白激酶磷酸酶-1表达的分析表明，在该人类模型中观察到的LPS耐受性与IRAK-1表达降低和IRAK-M表达升高有关。有趣的是，较低剂量的LPS（1 ng/kg）诱导LPS耐受性，伴有IRAK-M上调，但没有IRAK-1的消耗。全血中的体外研究表明，LPS引起的IRAK-M上调在很大程度上依赖于TNF-α。与体外刺激的全血相比，在人类内毒素血症模型中观察到的IRAK-M转录升高要大得多。总之，人类内毒素血症模型中的LPS耐受性与IRAK-M上调有关。
