Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells
Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells
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DOI：
10.1016/j.molimm.2008.02.010
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Onoe, Kazunori
中科院分区：
文献类型：
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作者：
Hirata, Noriyuki;Yanagawa, Yoshiki;Onoe, Kazunori
Toll样受体（TLR）配体，即脂多糖（LPS），诱导树突状细胞（DC）产生炎性和抗炎性细胞因子，包括白细胞介素（IL）-12、肿瘤坏死因子（TNF）-α和IL-10。炎症细胞因子与抗炎细胞因子的平衡似乎对控制免疫稳态至关重要。在本研究中，我们研究了TLR介导的调节炎症与抗炎细胞因子的生产使用小鼠骨髓来源的传统的DC。含有脂蛋白（TLR 2配体）的标准LPS（sLPS）诱导DC剧烈产生IL-10和IL-12 p40。高度纯化的LPS（ultra-pure LIPS，upLPS）也诱导IL-12 p40的剧烈产生，但显著低的IL-10产生。因此，通过TLR 2的信号缺陷似乎导致在用upLPS刺激时DC产生IL-10而不是IL-12 p40的显著减少。为了检验这种可能性，除了用upLPS刺激外，还用TLR 2的合成配体Pam 3CSK 4刺激DC。结果表明，单独的Pam 3CSK 4不能诱导IL-10产生。然而，Pam 3CSK 4协同增强upLPS诱导的DC产生IL-10，但既不增强IL-12 p40也不增强TNF-α。上调LPS刺激可显著激活DCs细胞外信号调节激酶（ERK）1/2、p38丝裂原活化蛋白激酶（MAPK）和c-jun N末端激酶（JNK）1/2。这些MAPK的upLPS诱导的活性通过用Pam 3CSK 4的额外刺激而显著增强。阻断p38 MAPK或JNK 1/2通路可完全抑制LPS和Pam 3CSK 4刺激DC产生IL-10的协同作用。因此，通过TLR 4和TLR 2协同刺激这些MAPK似乎诱导了鼠常规DC产生抗炎细胞因子的选择性协同作用。(c)2008爱思唯尔有限公司版权所有。
Toll-like receptor (TLR) ligands, i.e. lipopolysaccharide (LPS), induce dendritic cell (DC) production of both inflammatory and anti-inflammatory cytokines including interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and IL-10. The balance of inflammatory versus anti-inflammatory cytokines appears to be crucial to control immune homeostasis. In the present study, we investigated TLR-mediated regulation of inflammatory versus anti-inflammatory cytokine production using murine bone marrow derived conventional DCs. Standard LPS (sLPS) that contains lipoprotein, a TLR2 ligand, induced vigorous production of both IL-10 and IL-12 p40 by DCs. Highly purified LPS (ultra-pure LIPS, upLPS) also induced vigorous production of IL-12 p40, but markedly low IL-10 production. Thus, signal deficiency through TLR2 appeared to result in marked reduction in DC production of IL-10 but not IL-12 p40 upon stimulation with upLPS. To examine this possibility, DCs were stimulated with Pam3CSK4, a synthetic ligand of TLR2, in addition to stimulation with upLPS. It was shown that Pam3CSK4 alone failed to induce IL-10 production. However, Pam3CSK4 synergistically enhanced upLPS-induced DC production of IL-10 but neither IL-12 p40 nor TNF-alpha. Extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK)1/2 in DCs were significantly activated by upLPS stimulation. The upLPS-induced activities of these MAPKs were considerably enhanced by additional stimulation with Pam3CSK4. Blocking either p38 MAPK or JNK1/2 pathway completely inhibited the synergistic enhancement of the IL-10 production by DCs upon upLPS and Pam3CSK4 stimulation. Thus, cooperated stimulation of these MAPKs via TLR4 and TLR2 appeared to induce selective synergy in anti-inflammatory cytokine production by murine conventional DCs. (c) 2008 Elsevier Ltd. All rights reserved.