Th1-like cytokine induction by heat-killed Brucella abortus is dependent on triggering of TLR9
Th1-like cytokine induction by heat-killed Brucella abortus is dependent on triggering of TLR9
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DOI：
10.4049/jimmunol.175.6.3964
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发表时间：
2005-09-15
影响因子：
4.4
通讯作者：
Golding, B
中科院分区：
文献类型：
--
作者：
Huang, LY;Ishii, KJ;Golding, B
在这份报告中，我们首次提供证据，证明热致死流产布鲁氏菌(HKBA)背景下的细菌DNA与树突状细胞(DC)结合TLR9，导致Th1样细胞因子反应。这是基于以下发现：1)TLR9(-/-)小鼠的DC中取消了对IL-12p4O的诱导；2)被抑制性寡核苷酸阻断；3)被来自HKBA的细菌DNA模拟；以及4)被DNA酶或来自HKBA的DNA甲基化所抑制。此外，HKBA的作用可被氯喹抑制，这表明需要进行内体酸化，并支持HKBA的DNA与TLR9在衣壳水平上相互作用的观点，CpG寡核苷酸也是如此。除DC外，HKBA还可诱导巨噬细胞分泌IL-12p4O，这种作用完全依赖于MyD88，但仅部分依赖于TLR9。这可能解释了为什么在体内的HKBA效应在TLR9(-/-)小鼠中只有部分减少，而在MyD88(-/-)小鼠中则没有。由于DC与T细胞的密切相互作用，DC反应很可能是连接天然免疫和获得性免疫反应的关键，而巨噬细胞反应可能在增强NK细胞和旁观者免疫反应中发挥作用。除了IL-12p4O外，HKBA还以TLR9依赖的方式诱导其他Th1样细胞因子，即干扰素-α和干扰素-γ。这些细胞因子对预防病毒和细菌非常重要，而这些细胞因子的诱导作用也加强了HKBA作为疫苗的潜在载体的作用。
In this report we provide evidence, for the first time, that bacterial DNA in the context of heat-killed Brucella abortus (HKBA) engages TLR9 in dendritic cells (DC), resulting in a Th1-like cytokine response. This is based on the findings that HKBA induction of IL-12p4O is: 1) abolished in DC from TLR9(-/-) mice; 2) blocked by suppressive oligodeoxynucleotides; 3) simulated by bacterial DNA derived from HKBA; and 4) abrogated by DNase or methylation of the DNA from HKBA. Furthermore, the effect of HKBA can be inhibited by chloroquine, indicating that endosomal acidification is required and supporting the notion that DNA from HKBA is interacting with TLR9 at the level of the enclosome, as is the case with CpG oligodeoxynucleotides. In addition to DC, HKBA can elicit IL-12p4O secretion from macrophages, in which case the effect is wholly MyD88 dependent but only partially TLR9 dependent. This probably explains why HKBA effects in vivo are only partially reduced in TLR9(-/-), but absent in MyD88(-/-) mice. Because of their intimate interactions with T cells, the DC response is most likely to be critical for linking innate and adaptive immune responses, whereas the macrophage reaction may play a role in enhancing NK cell and bystander immune responses. In addition to IL-12p4O, HKBA induces other Th1-like cytokines, namely, IFN-alpha and IFN-gamma, in a TLR9-dependent manner. These cytokines are important in protection against viruses and bacteria, and their induction enhances HKBA as a potential carrier for vaccines.