Endotoxin-induced maturation of MyD88-deficient dendritic cells
Endotoxin-induced maturation of MyD88-deficient dendritic cells
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DOI：
10.4049/jimmunol.166.9.5688
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发表时间：
2001-05-01
影响因子：
4.4
通讯作者：
Akira, S
中科院分区：
文献类型：
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作者：
Kaisho, T;Takeuchi, O;Akira, S
LPS是革兰氏阴性菌细胞壁的主要成分，可以诱导多种生物反应，包括巨噬细胞产生细胞因子、B细胞增殖和内毒素休克。在 MyD88 缺陷小鼠中，所有这些都被完全消除，表明 MyD88 在 LPS 信号传导中的重要作用。然而，MyD88 缺陷细胞仍然表现出 NF-kappaB 和丝裂原激活蛋白激酶级联的激活，尽管这种激活的生物学意义尚不清楚。在这项研究中，我们研究了 LPS 对野生型和几种突变小鼠的树突状细胞 (DC) 的影响。 LPS 诱导 DC 产生细胞因子依赖于 MyD88。然而，LPS 可以诱导 MyD88 缺陷型 DC 的功能成熟，包括共刺激分子的上调和 APC 活性的增强。 MyD88 缺陷的 DC 无法响应细菌 DNA（Toll 样受体 (TLR)9 的配体）而成熟，表明 TLR 家族信号转导对 MyD88 的需求存在差异。 MyD88 依赖性和非依赖性途径起源于 TLR4 的胞质内区域，因为在该区域携带点突变的 C3H/HeJ 小鼠的 DC 中，细胞因子诱导和功能成熟均被取消。最后，体内分析表明，MyD88-而非TLR4-、缺陷性脾CD11c(+) DCs可以响应LPS上调其共刺激分子表达。总的来说，本研究提供了第一个证据，证明 TLR4 的 MyD88 独立通路下游可以导致功能性 DC 成熟，这对于先天免疫和适应性免疫之间的联系至关重要。
LPS, a major component of the cell wall of Gram-negative bacteria, can induce a variety of biological responses including cytokine production from macrophages, B cell proliferation, and endotoxin shock. All of them were completely abolished in MyD88-deficient mice, indicating the essential role of MyD88 in LPS signaling. However, MyD88-deficient cells still show activation of NF-kappaB and mitogen-activated protein kinase cascades, although the biological significance of this activation is not clear. In this study, we have examined the effects of LPS on dendritic cells (DCs) from wild-type and several mutant mice. LPS-induced cytokine production from DCs was dependent on MyD88. However, LPS could induce functional maturation of MyD88-deficient DCs, including up-regulation of costimulatory molecules and enhancement of APC activity. MyD88-deficient DCs could not maturate in response to bacterial DNA, the ligand for Toll-like receptor (TLR)9, indicating that MyD88 is differentially required for TLR family signaling. MyD88-dependent and -independent pathways originate at the intracytoplasmic region of TLR4, because both cytokine induction and functional maturation were abolished in DCs from C3H/HeJ mice carrying the point mutation in the region. Finally, in vivo analysis revealed that MyD88-, but not TLR4-, deficient splenic CD11c(+) DCs could up-regulate their costimulatory molecule expression in response to LPS. Collectively, the present study provides the first evidence that the MyD88-independent pathway downstrem of TLR4 can lead to functional DC maturation, which is critical for a link between innate and adaptive immunity.