Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-β
Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-β
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DOI：
10.1016/j.bbrc.2004.12.184
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发表时间：
2005-03-11
影响因子：
3.1
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Hirotani, T;Yamamoto, M;Akira, S
巨噬细胞通过 Toll 样受体 4 识别脂多糖 (LPS)，并通过诱导各种基因的表达来激活炎症反应。 TLR4 通过含有 TIR 结构域的接头分子、MyD88 和含有诱导 IFN-P (TRIF) 的接头的 Toll/IL-I 结构域来激活细胞内信号传导途径。尽管缺乏 MyD88 或 TRIF 的巨噬细胞显示出细胞因子生成受损，但这些细胞中的 LPS 仍会激活细胞内信号分子。在本研究中，我们采用 cDNA 微阵列来研究 MyD88 和 TRIF 在 LPS 刺激诱导的基因表达中的贡献。野生型巨噬细胞响应 LPS 诱导 148 个基因，而缺乏 MyD88 和 TRIF 的巨噬细胞不会上调任何响应 LPS 的基因。令人惊讶的是，80 个 LPS 诱导基因被 MyD88 或 TRIF 过度调控。相比之下，促炎细胞因子和趋化因子仅受到 MyD88 或 TRIF 的严格调节。仅受 MyD88 严格调控的基因往往会在 LPS 刺激后快速诱导，并受到 mRNA 稳定性和转录的调控。已知由 I 型干扰素诱导的基因的表达完全依赖于 TRIF。总的来说，MyD88 和 TRIF 在 LPS 诱导的基因表达中发挥着冗余且不同的作用。 (C) 2005 Elsevier Inc. 保留所有权利。
Macrophages recognize lipopolysaccharide (LPS) by Toll-like receptor 4 and activate inflammatory responses by inducing expression of various genes. TLR4 activates intracellular signaling pathways via TIR domain containing adaptor molecules, MyD88, and Toll/IL-I domain containing adaptor inducing IFN-P (TRIF). Although macrophages lacking MyD88 or TRIF showed impaired cytokine production, activation of intracellular signaling molecules still occurred in response to LPS in these cells. In the present study, we implemented cDNA microarrays to investigate the contribution of MyD88 and TRIF in gene expression induced by LPS stimulation. Whereas wild-type macrophages induced 148 genes in response to LPS, macrophages lacking both MyD88 and TRIF did not upregulate any genes in response to LPS. Surprisingly, 80 LPS-inducible genes were redundantly regulated by either MyD88 or TRIF. In contrast, proinflammatory cytokines and chemokines were critically regulated by MyD88 or TRIF alone. Genes critically regulated by MyD88 alone tend to be induced quickly after LPS stimulation and regulated by mRNA stability as well as transcription. Genes known to be induced by type I interferons were simply dependent on TRIF for their expression. Taken together, MyD88 and TRIF play both redundant and distinct roles in LPS-induced gene expression. (C) 2005 Elsevier Inc. All rights reserved.