Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.
Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.
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巨噬细胞对Francisella Novicida感染的促炎反应受到船的调节。
DOI：
10.1371/journal.ppat.0020071
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发表时间：
2006-07
期刊：
影响因子：
6.7
通讯作者：
Tridandapani S
中科院分区：
文献类型：
--
作者：
Parsa KV;Ganesan LP;Rajaram MV;Gavrilin MA;Balagopal A;Mohapatra NP;Wewers MD;Schlesinger LS;Gunn JS;Tridandapani S
图拉氏方济氏菌是一种主要感染巨噬细胞和单核细胞的革兰氏阴性兼性胞内病原菌，是图拉热症的病原体。巨噬细胞对图拉氏丝虫感染的反应包括产生促炎细胞因子，如白介素12，这是免疫抵御感染的关键。调节这些炎症介质产生的分子机制还知之甚少。在这里，我们报道了含有SH2结构域的肌醇磷酸酶(SHIP)在遗传上相关的F.novicida感染原代小鼠巨噬细胞时被磷酸化，并负调控F.novicida诱导的细胞因子的产生。对分子细节的分析表明，新城疫霉菌感染除了激活MAP激酶外，还激活了这些细胞中的磷脂酰肌醇3-激酶(PI3K)/Akt通路。有趣的是，SHIP缺乏的巨噬细胞在新城疫霉菌感染时表现出增强的Akt激活，这表明在没有SHIP的情况下PI3K依赖的激活途径增加。抑制PI3K/AKT可通过抑制NFκB抑制新城疫霉菌诱导的细胞因子的产生，而缺乏SHIP的巨噬细胞表现出由NFκB驱动的基因转录增强，而SHIP的过表达则导致NFκB的活性降低。因此，我们认为SHIP通过拮抗PI3K/AKT通路和抑制NFκB介导的基因转录来负性调节新月弯孢杆菌诱导的炎性细胞因子反应。对肌醇磷脂信号的详细分析可能为更好地理解图拉热症的发病机制提供有价值的线索。图拉氏方济氏菌是一种细胞内的革兰氏阴性细菌，会导致图拉热症。细菌感染巨噬细胞，并在宿主细胞内复制。巨噬细胞通过产生促炎细胞因子来对抗感染。参与宿主细胞反应的细胞内信号事件尚不完全清楚。人们对这些反应的调控机制知之甚少。在这项研究中，作者定义了肌醇磷酸酶SHIP在方济各氏菌感染小鼠巨噬细胞过程中的负调控作用。这项研究表明，SHIP在感染细胞中被激活，并下调促炎细胞因子的产生。作者研究了这种负调控的分子机制，并表明SHIP作用于参与炎性细胞因子基因转录的重要转录因子NFκB的上游，并抑制其激活。SHIP的这种作用似乎是通过调节PI3激酶途径来实现的。这项研究为SHIP在调节巨噬细胞对弗朗西斯杆菌的炎症反应中发挥了新的关键作用。
Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida–induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida–induced cytokine production through the inhibition of NFκB. Consistently, macrophages lacking SHIP displayed enhanced NFκB-driven gene transcription, whereas overexpression of SHIP led to decreased NFκB activation. Thus, we propose that SHIP negatively regulates F. novicida–induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFκB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia. Francisella tularensis is an intracellular Gram-negative bacterium that causes the disease tularemia. The bacteria infect macrophages and replicate within the host cell. Macrophages respond to the infection by producing pro-inflammatory cytokines in an effort to combat the infection. The intracellular signaling events that are involved in host cell responses are not fully understood. Much less understood are mechanisms that regulate these responses. In this study, the authors define a negative regulatory role for the inositol phosphatase SHIP during Francisella infection of mouse macrophages. The study demonstrates that SHIP is activated in infected cells and serves to down-regulate pro-inflammatory cytokine production. The authors have examined the molecular mechanism underlying this negative regulation, and show that SHIP acts upstream of NFκB, an important transcription factor involved in inflammatory cytokine gene transcription, and dampens its activation. This effect of SHIP appears to be mediated through the regulation of the PI3 kinase pathway. This study establishes a novel and critical role for SHIP in the regulation of macrophage inflammatory response to Francisella bacteria.
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影响因子：
3.2
作者：
Nano, FE;Zhang, N;Elkins, KL
通讯作者：
Elkins, KL
影响因子：
64.5
作者：
HORWITZ, MA
通讯作者：
HORWITZ, MA
DOI：
10.1073/pnas.0504271103
发表时间：
2006-01-03
影响因子：
11.1
作者：
Gavrilin, MA;Bouakl, IJ;Wewers, MD
通讯作者：
Wewers, MD
影响因子：
3.1
作者：
Golovliov, I;Baranov, V;Sjöstedt, A
通讯作者：
Sjöstedt, A
影响因子：
4.8
作者：
Ganesan, LP;Wei, G;Tridandapani, S
通讯作者：
Tridandapani, S