Campylobacter jejuni-Induced Activation of Dendritic Cells Involves Cooperative Signaling through Toll-Like Receptor 4 (TLR4)-MyD88 and TLR4-TRIF Axes
Campylobacter jejuni-Induced Activation of Dendritic Cells Involves Cooperative Signaling through Toll-Like Receptor 4 (TLR4)-MyD88 and TLR4-TRIF Axes
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DOI：
10.1128/iai.01562-08
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发表时间：
2009-06-01
影响因子：
3.1
通讯作者：
Mansfield, Linda S.
中科院分区：
文献类型：
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作者：
Rathinam, Vijay A. K.;Appledorn, Daniel M.;Mansfield, Linda S.
空肠弯曲杆菌是人类肠炎的重要病因，并与自身免疫性疾病的发展有关。最近我们发现，空肠梭菌感染小鼠树突状细胞（DC）可激活DC并诱导弯曲杆菌特异性th1效应反应。toll样受体（TLR）通过髓样分化因子88 （MyD88）和/或toll -白细胞介素1 （IL-1）受体结构域诱导β干扰素（ifn - γ） （TRIF）信号传导在诱导对病原体的免疫中至关重要。在本研究中，我们研究了TLR2、TLR4、MyD88和TRIF信号在C. jejunii诱导的dc炎症激活中的作用。TLR2、TLR4、MyD88和TRIF缺乏严重损害了空肠c攻击后主要组织相容性复合体II类和共刺激分子的DC上调。同样，与野生型dc相比，C. jejunii诱导的TLR2（-/-）、TLR4（-/-）、MyD88（-/-）和TRIF-/- dc中IL-12、IL-6和肿瘤坏死因子α的分泌明显受到抑制；然而，MyD88（-/-）、TRIF-/-和TLR4(-/-) DCs的抑制程度大于TLR2(-/-) DCs。此外，空肠c以tlr4 - trf依赖的方式诱导dc分泌干扰素调节因子3磷酸化和ifn - γ，进一步证明空肠c激活了这一途径。重要的是，TLR2、TLR4、MyD88和TRIF缺陷都显著损害了C. jejunii感染的dc的th1启动能力。因此，我们的研究结果表明，通过TLR4-MyD88和TLR4-TRIF轴的协同信号传导代表了一种介导空肠杆菌诱导的DCs炎症反应的新机制。据我们所知，这种机制以前还没有在一个完整的细菌中得到证实。
Campylobacter jejuni is an important cause of human enteritis and has been linked to the development of autoimmune diseases. Recently we showed that infection of murine dendritic cells (DCs) with C. jejuni resulted in DC activation and induction of Campylobacter-specific Th1-effector responses. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) and/or Toll-interleukin 1 (IL-1) receptor domain-containing adaptor-inducing beta interferon (IFN-gamma) (TRIF) is critical in inducing immunity against pathogens. In this study, we investigated the role of TLR2, TLR4, MyD88, and TRIF signaling in C. jejuni-induced inflammatory activation of DCs. DC upregulation of major histocompatibility complex class II and costimulatory molecules after C. jejuni challenge was profoundly impaired by TLR2, TLR4, MyD88, and TRIF deficiencies. Similarly, C. jejuni-induced secretion of IL-12, IL-6, and tumor necrosis factor alpha was significantly inhibited in TLR2(-/-), TLR4(-/-), MyD88(-/-), and TRIF-/- DCs compared to that in wild-type DCs; however, the magnitude of inhibition was greater in MyD88(-/-), TRIF-/-, and TLR4(-/-) DCs than in TLR2(-/-) DCs. Furthermore, C. jejuni induced interferon regulatory factor 3 phosphorylation and IFN-gamma secretion by DCs in a TLR4-TRIF-dependent fashion, further demonstrating activation of this pathway by C. jejuni. Importantly, TLR2, TLR4, MyD88, and TRIF deficiencies all markedly impaired the Th1-priming ability of C. jejuni-infected DCs. Thus, our results show that cooperative signaling through the TLR4-MyD88 and TLR4-TRIF axes represents a novel mechanism mediating C. jejuni-induced inflammatory responses of DCs. To our knowledge, such a mechanism has not been demonstrated previously for an intact bacterium.