STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection1
STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection1
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STAT4 是针对肺部克雷伯氏菌感染的早期先天免疫反应的关键介质1
作者：
Jane C. Deng;Xianying Zeng;M. Newstead;T. Moore;W. Tsai;V. Thannickal;T. Standiford
细菌性肺炎是美国发病率和死亡率的主要原因。有效的先天免疫应答对于从肺部清除细菌至关重要。IL-12是先天免疫中的关键T1细胞因子，通过STAT 4发出信号。因此，了解STAT 4如何介导针对细菌病原体的肺部免疫应答将对开发以增强先天免疫为目标的合理免疫疗法具有重要意义。我们对野生型BALB/c和STAT 4基因敲除（STAT 4 −/−）小鼠进行了气管内注射肺炎克雷伯氏菌。与野生型对照组相比，经气管内注射克雷伯氏菌后，STAT 4 −/−小鼠的存活率降低，这与较高的肺和血液细菌负荷有关。STAT 4 −/−动物也表现出肺IFN-γ产生受损和促炎细胞因子水平降低，包括ELR-CXC趋化因子IFN-γ诱导蛋白-10和IFN-γ诱导的单核因子。尽管感染后STAT 4 −/−和野生型动物之间的肺白细胞总数相似，但与感染的野生型小鼠相比，从感染的STAT 4 −/−小鼠中分离的肺泡巨噬细胞产生的促炎细胞因子（包括IFN-γ）减少。IFN-γ的肺内过表达伴随IFN-γ的全身给药部分逆转了在STAT 4 −/−小鼠中观察到的免疫缺陷，从而改善了血液中的细菌清除。总的来说，这些研究表明，STAT 4是产生有效的先天宿主防御肺细菌病原体所必需的。
Bacterial pneumonia is a leading cause of morbidity and mortality in the U.S. An effective innate immune response is critical for the clearance of bacteria from the lungs. IL-12, a key T1 cytokine in innate immunity, signals through STAT4. Thus, understanding how STAT4 mediates pulmonary immune responses against bacterial pathogens will have important implications for the development of rational immunotherapy targeted at augmenting innate immunity. We intratracheally administered Klebsiella pneumoniae to wild-type BALB/c and STAT4 knockout (STAT4−/−) mice. Compared with wild-type controls, STAT4−/− mice had decreased survival following intratracheal Klebsiella administration, which was associated with a higher lung and blood bacterial burden. STAT4−/− animals also displayed impaired pulmonary IFN-γ production and decreased levels of proinflammatory cytokines, including the ELR− CXC chemokines IFN-γ-inducible protein-10 and monokine induced by IFN-γ. Although total lung leukocyte populations were similar between STAT4−/− and wild-type animals following infection, alveolar macrophages isolated from infected STAT4−/− mice had decreased production of proinflammatory cytokines, including IFN-γ, compared with infected wild-type mice. The intrapulmonary overexpression of IFN-γ concomitant with the systemic administration of IFN-γ partially reversed the immune deficits observed in STAT4−/− mice, resulting in improved bacterial clearance from the blood. Collectively, these studies demonstrate that STAT4 is required for the generation of an effective innate host defense against bacterial pathogens of the lung.
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DOI：
10.1016/s0021-9258(18)53940-5
发表时间：
1993-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Lorsbach;W. Murphy;C. Lowenstein;S. Snyder;S. Russell
通讯作者：
R. Lorsbach;W. Murphy;C. Lowenstein;S. Snyder;S. Russell
肺内肿瘤坏死因子基因治疗可增加小鼠革兰氏阴性肺炎的细菌清除率和存活率。
影响因子：
4.2
作者：
Standiford,TJ;Wilkowski,JM;Sisson,TH;Hattori,N;Mehrad,B;Bucknell,KA;Moore,TA
通讯作者：
Moore,TA
IL-12 基因疗法可保护患有致命克雷伯氏菌肺炎的小鼠。
DOI：
--
发表时间：
1996
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Greenberger,MJ;Kunkel,SL;Strieter,RM;Lukacs,NW;Bramson,J;Gauldie,J;Graham,FL;Hitt,M;Danforth,JM;Standiford,TJ
通讯作者：
Standiford,TJ
影响因子：
20.3
作者：
Gollob, JA;Murphy, EA;Frank, DA
通讯作者：
Frank, DA
DOI：
10.1152/ajplung.00216.2001
发表时间：
2002-05-01
影响因子：
4.9
作者：
Hickman-Davis, JM;O'Reilly, P;Matalon, S
通讯作者：
Matalon, S