Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways
Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways
复制标题
DOI：
10.1093/intimm/dxl148
复制
发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Nakanishi, Kenji
中科院分区：
文献类型：
--
作者：
Sawaki, Junko;Tsutsui, Hiroko;Nakanishi, Kenji
已经充分确定，IL-18 R和toll样受体（TLR）介导的信号传导共享由信号衔接子MyD 88介导的共同信号通路，并且IL-18与IL-12协同用于NK细胞产生IFN-γ。在这里，我们研究了TLR激动剂是否可以取代IL-18用于NK细胞产生IFN-γ。新鲜分离的NK细胞具有由TLR 4/MD 2复合物和CD 14组成的功能性LPS受体，并且还表达其它各种TLR。肝CD 3（-）DX 5（+）NK细胞仅在与IL-12共刺激时响应于TLR 2或TLR 7激动剂产生IFN-γ，表明TLR激动剂与IL-12协同产生IFN-γ。tlr 2（-/-）或tlr 7（-/-）NK细胞不能分别响应于IL-12加TLR 2或TLR 7配体产生IFN-γ，表明需要相应的TLR。此外，在用这些组合刺激时，野生型NK细胞也产生1型趋化因子，例如CCL 3、CCL 4和CCL 5。当与来自幼稚小鼠的NK细胞相比时，来自细菌（例如痤疮丙酸杆菌）接种的rag 2（-/-）小鼠的NK细胞显示出显著增强的产生这些CC趋化因子和IFN-γ的能力，这表明微生物感染增强了NK细胞对TLR激动剂的响应性。这些结果表明，在微生物感染时，巨噬细胞产生IL-12，其使NK细胞对TLR激动剂高度响应以产生IFN-γ和趋化因子，其可能进而募集并完全激活巨噬细胞，导致炎症灶的发展，这可能是有效的微生物根除所必需的。因此，NK细胞与T细胞一样，与巨噬细胞合作诱导协调的免疫应答，以在早期感染阶段显示出有效的宿主防御作用。
It is well established that IL-18R- and toll-like receptor (TLR)-mediated signalings share a common signal pathway mediated by signal adaptor, MyD88, and that IL-18 synergizes with IL-12 for IFN-gamma production by NK cells. Here, we investigated whether TLR agonists can replace IL-18 for production of IFN-gamma by NK cells. Freshly isolated NK cells possessed functional LPS receptor composed of TLR4/MD2 complex and of CD14, and also expressed other various tlrs. Hepatic CD3(-)DX5(+) NK cells produced IFN-gamma in response to TLR2 or TLR7 agonists only when co-stimulated with IL-12, indicating that TLR agonists synergize with IL-12 for IFN-gamma. The tlr2(-/-) or tlr7(-/-) NK cells could not produce IFN-gamma in response to IL-12 plus TLR2 or TLR7 ligands, respectively, indicating requirement of the corresponding TLRs. Furthermore, upon stimulation with these combinations, wild-type NK cells produced type 1 chemokines, such as CCL3, CCL4 and CCL5 as well. NK cells from bacterium (e.g. Propionibacterium acnes)-inoculated rag2(-/-) mice, when compared with those from naive mice, exhibited significantly enhanced capacity to produce these CC chemokines and IFN-gamma, suggesting that microbial infection enhances responsiveness of NK cells to TLR agonists. These results indicate that upon microbial infection, macrophages produce IL-12 that renders NK cells highly responsive to TLR agonists to produce IFN-gamma and chemokines, which might in turn recruit and fully activate macrophages, leading to the development of inflammatory foci presumably necessary for efficient microbial eradication. Thus, NK cells, like T cells, induce orchestrated immune responses in collaboration with macrophages to show potent host defense effects during early infectious phase.