Institute of Immunology, Rikshospitalet University Hospital, University of Oslo, N-0027 Oslo, Norway.
Mol Immunol. 2010 May;47(9):1774-82. doi: 10.1016/j.molimm.2010.02.026. Epub 2010 Mar 23.
Inhibition of the inappropriate and excessive inflammatory response has been a main issue in sepsis-related research. Historically, TNF-alpha and IL-1 beta have been postulated as key mediators in sepsis, but selective inhibition of these cytokines has failed in clinical trials. Recently it was found that inhibition of upstream recognition by complement and CD14 could efficiently reduce Escherichia coli (E. coli)-induced inflammation. An ex vivo model with lepirudin-anticoagulated human whole blood was used to explore the significance of selective inhibition of TNF-alpha and IL-1 beta in E. coli-induced inflammation. The effect of TNF-alpha, IL-1 beta, complement and CD14 on the inflammatory response was assessed by adding highly specific neutralizing agents to these mediators. Proinflammatory cytokines, expression of CD11b and oxidative burst were measured. The controls included relevant isotype-matched immunoglobulins and peptides. Selective inhibition of TNF-alpha or IL-1 beta had no impact on E. coli-induced release of proinflammatory cytokines, CD11b-upregulation or oxidative burst. In contrast, the combined inhibition of complement and CD14 virtually abolished these responses. These data suggest that both TNF-alpha and IL-1 beta are downstream mediators and as single mediators play a limited role within the complex inflammatory reactions induced by E. coli.
抑制不适当和过度的炎症反应一直是与脓毒症相关研究的主要问题。从历史上看，TNF-α 和 IL-1β 被认为是脓毒症的关键介质，但这些细胞因子的选择性抑制在临床试验中失败了。最近发现，通过补体和 CD14 的上游识别抑制可以有效地减少大肠杆菌（E. coli）诱导的炎症。使用 lepirudin 抗凝的人全血的离体模型来探索选择性抑制 TNF-α 和 IL-1β 在大肠杆菌诱导的炎症中的意义。通过向这些介质中添加高度特异性的中和剂来评估 TNF-α、IL-1β、补体和 CD14 对炎症反应的影响。测量促炎细胞因子、CD11b 的表达和氧化爆发。对照组包括相关的同种型匹配的免疫球蛋白和肽。TNF-α 或 IL-1β 的选择性抑制对大肠杆菌诱导的促炎细胞因子、CD11b 上调或氧化爆发的释放没有影响。相比之下，补体和 CD14 的联合抑制几乎完全消除了这些反应。这些数据表明，TNF-α 和 IL-1β 都是下游介质，作为单一介质，在大肠杆菌诱导的复杂炎症反应中作用有限。
