Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.
Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.
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DOI：
10.1126/scisignal.2000955
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发表时间：
2010-08-17
影响因子：
7.3
通讯作者：
Murray PJ
中科院分区：
文献类型：
--
作者：
Qualls JE;Neale G;Smith AM;Koo MS;DeFreitas AA;Zhang H;Kaplan G;Watowich SS;Murray PJ
由巨噬细胞产生的一氧化氮（NO）对宿主组织和入侵病原体具有毒性，因此其调节对于抑制宿主细胞毒性至关重要。巨噬细胞吞噬酶1（Macrophage glycoproteinase 1，Arg 1）通过与NO吞噬酶竞争NO吞噬酶和精氨酸酶的共同底物精氨酸来抑制NO的产生。巨噬细胞Arg 1的产生受两条信号转导通路的调控。首先，依赖于Toll样受体（TLR）衔接蛋白髓样分化标志物88（MyD 88）的途径诱导Arg 1在细胞内感染中的表达，而第二条途径，这是依赖于信号转导和转录激活因子6（STAT 6）是必需的Arg 1在交替激活的巨噬细胞的表达。我们发现，分枝杆菌感染的巨噬细胞产生的可溶性因子，包括白细胞介素-6（IL-6），IL-10，和粒细胞集落刺激因子（G-CSF），诱导Arg 1的自分泌-旁分泌的方式表达。我们进一步确定Arg 1的表达是由MyD 88依赖的IL-6、IL-10和G-CSF的产生控制的，而不是由细胞内在的MyD 88信号传导到Arg 1。我们的数据表明，MyD 88依赖性途径，诱导表达Arg 1感染后，分枝杆菌需要激活STAT 3，并可能导致在肉芽肿的免疫抑制生态位的发展，因为在周围未感染的巨噬细胞中的Arg 1的诱导生产。
Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) inhibits the production of NO by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control the production of Arg1 in macrophages. First, a pathway dependent on the Toll-like receptor (TLR) adaptor protein myeloid differentiation marker 88 (MyD88) induces the expression of Arg1 in intracellular infections, whereas a second pathway, which is dependent on signal transducer and activator of transcription 6 (STAT6) is required for the expression of Arg1 in alternatively-activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony–stimulating factor (G-CSF), that induced the expression of Arg1 in an autocrine-paracrine manner. We further established that Arg1 expression was controlled by the MyD88-dependent production of IL-6, IL-10, and G-CSF rather than by cell-intrinsic MyD88 signaling to Arg1. Our data reveal that the MyD88-dependent pathway that induces expression of Arg1 after infection by mycobacteria requires the activation of STAT3 and may result in the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1084/jem.175.4.1111
发表时间：
1992-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chan J;Xing Y;Magliozzo RS;Bloom BR
通讯作者：
Bloom BR
DOI：
10.1073/pnas.0604283103
发表时间：
2006-10-17
影响因子：
11.1
作者：
Newton, Sandra M.;Smith, Rebecca J.;Wilkinson, Robert J.
通讯作者：
Wilkinson, Robert J.
影响因子：
3.1
作者：
Ladel, CH;Blum, C;Kaufmann, SHE
通讯作者：
Kaufmann, SHE
影响因子：
4.4
作者：
Nagabhushanam, V;Solache, A;Ernst, JD
通讯作者：
Ernst, JD