Distinct pathways of LPS-induced NF-κB activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP
Distinct pathways of LPS-induced NF-κB activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP
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DOI：
10.1182/blood-2003-04-1356
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发表时间：
2004-03-15
期刊：
影响因子：
20.3
通讯作者：
Foxwell, BM
中科院分区：
文献类型：
--
作者：
Andreakos, E;Sacre, SM;Foxwell, BM
脓毒症时脂多糖(LPS)如何通过Toll样受体(TLRs)诱导核因子(NF)-kappaB和炎性细胞因子尚不清楚。这一过程的主要候选者是髓系分化蛋白88(MyD88)和MyD88适配子样/含TIR结构域的适配子蛋白(MAL/TIRAP)，但它们的作用还需要进一步确定。在这里，我们研究了MyD88和MAL/TIRAP作为生理相关系统在非髓系和髓系来源的原代人类细胞中的作用。我们发现，MyD88和MAL/TIRAP在脂多糖诱导的IkappaBalpha磷酸化、核因子-kappaB激活以及成纤维细胞和内皮细胞产生白介素6(IL-6)或IL-8的途径中是必不可少的，这一途径也需要IKK2。相反，在巨噬细胞中，核因子-kappaB的激活或肿瘤坏死因子α(TNFpha)、IL-6或IL-8的产生既不需要MyD88、MAL/TIRAP，也不需要IkappaB激酶2(IKK2)，尽管MAL/TIRAP仍然参与干扰素β(IFNbeta)的产生。与巨噬细胞而不是成纤维细胞或内皮细胞一样，TLR4在细胞表面高水平表达，TLR4的中和而不是TLR2阻断内毒素信号传导，这可能是TLR4不同用途的原因。这些观察首次证明了由选择性利用TLR4、MyD88、MAL/TIRAP和IKK2定义的在人髓系和非髓系细胞中存在两条不同的途径来诱导NF-kappaB的激活和细胞因子的产生，并揭示了一个以前没有预料到的复杂性。(C)2004年，由美国血液病学会提供。
How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)-kappaB and inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced IkappaBalpha phosphorylation, NF-kappaB activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor IkappaB kinase 2 (IKK2) are required for NF-kappaB activation or tumor necrosis factor alpha (TNFalpha), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon beta (IFNbeta). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-kappaB activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected. (C) 2004 by The American Society of Hematology.