Tobacco smoking inhibits expression of proinflammatory Cytokines and activation of IL-1R-Associated kinase, p38, and NF-κB in alveolar macrophages stimulated with TLR2 and TLR4 Agonists
Tobacco smoking inhibits expression of proinflammatory Cytokines and activation of IL-1R-Associated kinase, p38, and NF-κB in alveolar macrophages stimulated with TLR2 and TLR4 Agonists
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DOI：
10.4049/jimmunol.179.9.6097
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Medvedev, Andrei E.
中科院分区：
文献类型：
--
作者：
Chen, Haiyan;Cowan, Mark J.;Medvedev, Andrei E.
吸烟与肺功能受损和感染发生率增加有关;然而，对这些现象的机制知之甚少。在这项研究中，我们研究了吸烟者的肺泡巨噬细胞（AM）是否表现出受损的细菌组分通过TLR 2和TLR 4的传感，并确定吸烟对TLR 2，TLR 4和辅助受体的表达水平的影响，以及信号中间体的激活。吸烟者AM的基因表达和促炎细胞因子分泌减少（TNF-α、IL-1 β、IL-6）和趋化因子（RANTES和IL-8）刺激后，与TLR 2和TLR 4激动剂，S-[2，3-双（棕榈酰氧基）-（2-RS）-丙基-N-棕榈酰-（R）-Cys-（S）-Ser-Lys 4-OH三盐酸盐（PaM 3CYS），和LPS，而抗炎细胞因子（IL-10和IL-1受体拮抗剂）的表达不受影响。用聚肌胞苷酸激活TLR 3导致吸烟者AM中相当或甚至更高的细胞因子应答，表明吸烟诱导的抑制并不影响所有TLR。在从吸烟者和非吸烟者获得的PBMC和纯化的单核细胞中检测到相当的细胞因子和趋化因子表达，表明吸烟的抑制作用仅限于肺。吸烟者AM中TLR 2/4诱导的IL-111相关激酶-1（IRAK-1）和p38磷酸化以及NF-κ B活化受到抑制，而TLR 2、TLR 4、CD 14、MD-2 mRNA水平和TLR 4蛋白表达没有改变。这些数据表明，在后受体水平的信号中间体的表达和/或活动的变化占吸烟诱导的免疫抑制。因此，AM暴露于烟草烟雾诱导类似于内毒素耐受性的低反应状态，如通过抑制TLR 2/4诱导的促炎细胞因子、趋化因子的表达以及IRAK-1、p38和NF-κ B的活化受损所表现的，导致促炎介质的表达受到抑制。
Tobacco smoking has been associated with impaired pulmonary functions and increased incidence of infections; however, mechanisms that underlie these phenomena are poorly understood. In this study, we examined whether smokers' alveolar macrophages (AM) exhibit impaired sensing of bacterial components via TLR2 and TLR4 and determined the effect of smoking on expression levels of TLR2, TLR4 and coreceptors, and activation of signaling intermediates. Smokers' AMs exhibited reduced gene expression and secretion of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and chemokines (RANTES and IL-8) upon stimulation with TLR2 and TLR4 agonists, S-[2,3-bis(palmitoyloxy)-(2-RS)-propyll-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH trihydrochloride (PaM3CYS), and LPS, whereas expression of anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) was not affected. TLR3 activation with polyinosinic-polycytidylic acid led to comparable or even higher cytokine responses in smokers' AMs, indicating that smoking-induced suppression does not affect all TLRs. Comparable expression of cytokines and chemokines was detected in PBMC and purified monocytes obtained from smokers and nonsmokers, demonstrating that the suppressive effect of smoking is restricted to the lung. TLR2/4-inducible IL-111-associated kinase-1 (IRAK-1) and p38 phosphorylation and NF-kappa B activation was suppressed in smokers' AMs, whereas TLR2, TLR4, CD14, MD-2 mRNA levels, and TLR4 protein expression were not altered. These data suggest that changes in expression and/or activities of signaling intermediates at the postreceptor level account for smoking-induced immunosuppression. Thus, exposure of AMs to tobacco smoke induces a hyporesponsive state similar to endotoxin tolerance as manifested by inhibited TLR2/4-induced expression of proinflammatory cytokines, chemokines, and impaired activation of IRAK-1, p38, and NF-kappa B, resulting in suppressed expression of proinflammatory mediators.