Protein kinase D1 is essential for the proinflammatory response induced by hypersensitivity pneumonitis-causing thermophilic actinomycetes Saccharopolyspora rectivirgula.
Protein kinase D1 is essential for the proinflammatory response induced by hypersensitivity pneumonitis-causing thermophilic actinomycetes Saccharopolyspora rectivirgula.
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DOI：
10.4049/jimmunol.0903718
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Yi AK
中科院分区：
文献类型：
--
作者：
Kim YI;Park JE;Brand DD;Fitzpatrick EA;Yi AK
过敏性肺炎是一种间质性肺病，由肺部反复接触各种有机抗原引起，包括直弯孢霉（SR，农民肺疾病的病原体）。尽管促炎介质在疾病发病机制中的作用已有相对充分的文献记载，但针对致病微生物引发促炎反应所涉及的机制以及参与宿主免疫防御的信号分子的作用尚未完全阐明。在本研究中，我们发现SR在体外和体内均可诱导肺细胞中蛋白激酶D1（PKD1）的活化。SR对PKD1的激活依赖于MyD88。通过药理学PKD抑制剂Gö6976抑制PKD，以及通过小干扰RNA沉默PKD1表达，结果表明PKD1对于SR介导的丝裂原活化蛋白激酶（MAPKs）和核因子-κB（NF - κB）的活化以及各种促炎细胞因子和趋化因子的表达是必不可少的。此外，与对照组相比，用Gö6976预处理的小鼠在肺部接触SR后，支气管肺泡灌洗液和间质性肺组织中的肺泡炎和中性粒细胞流入显著受到抑制，肺中的髓过氧化物酶活性也大幅降低。这些结果表明PKD1对于SR介导的肺部促炎免疫反应和中性粒细胞流入至关重要。我们的研究结果还暗示PKD1可能是在微生物抗原引起的过敏性肺炎发展中起调节作用的关键因素之一，并且抑制PKD1的激活可能是控制微生物抗原诱导的过敏性肺炎的一种有效方法。
Hypersensitivity pneumonitis is an interstitial lung disease that results from repeated pulmonary exposure to various organic antigens, including Saccharopolyspora rectivirgula (SR, the causative agent of farmer's lung disease). Although the contributions of pro-inflammatory mediators to the disease pathogenesis are relatively well documented, the mechanism(s) involved in initiation of pro-inflammatory responses against the causative microorganisms, and the contribution of signaling molecules involved in host immune defense have not been fully elucidated. In the present study, we found that SR induces activation of protein kinase D1 (PKD1) in lung cells in vitro and in vivo. Activation of PKD1 by SR was dependent on MyD88. Inhibition of PKD by pharmacological PKD inhibitor Gö6976, and silencing of PKD1 expression by siRNA, revealed that PKD1 is indispensable for SR-mediated activation of MAPKs and NF-κB and expression of various pro-inflammatory cytokines and chemokines. In addition, compared to controls, mice pretreated with Gö6976 showed significantly suppressed alveolitis and neutrophil influx in bronchial alveolar lavage fluid and interstitial lung tissue, and substantially decreased myeloperoxidase activity in the lung after pulmonary exposure to SR. These results demonstrate that PKD1 is essential for SR-mediated pro-inflammatory immune responses and neutrophil influx in the lung. Our findings also imply the possibility that PKD1 might be one of the critical factors that play a regulatory role in development of hypersensitivity pneumonitis caused by microbial antigens, and that inhibition of PKD1 activation could be an effective way to control microbial antigen-induced hypersensitivity pneumonitis.
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DOI：
10.1084/jem.192.4.595
发表时间：
2000-08-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Häcker H;Vabulas RM;Takeuchi O;Hoshino K;Akira S;Wagner H
通讯作者：
Wagner H
影响因子：
5.4
作者：
Nance, S;Cross, R;Fitzpatrick, EA
通讯作者：
Fitzpatrick, EA
影响因子：
5.3
作者：
Conze, Dietrich B.;Wu, Chuan-Jin;Ashwell, Jonathan D.
通讯作者：
Ashwell, Jonathan D.
影响因子：
15.9
作者：
Gudmundsson, G;Hunninghake, GW
通讯作者：
Hunninghake, GW
影响因子：
64.8
作者：
Hemmi, H;Takeuchi, O;Akira, S
通讯作者：
Akira, S