MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation
MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation
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DOI：
10.1128/iai.00186-12
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发表时间：
2013-03-01
影响因子：
3.1
通讯作者：
Haslam, David B.
中科院分区：
文献类型：
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作者：
Bobo, Linda D.;El Feghaly, Rana E.;Haslam, David B.
艰难梭菌感染（CDI）导致毒素诱导的上皮损伤和明显的肠道炎症。肠道炎症的粪便标志物与CDI疾病的严重程度相关，但对炎症反应的调节知之甚少。先前的研究表明，艰难梭菌毒素TcdA激活组织培养细胞和小鼠髂骨中的p38激酶，导致白细胞介素-8 （IL-8）的释放。在这里，我们研究了磷酸化丝裂原活化蛋白激酶（MAPK）活化蛋白激酶（MK2激酶，pMK2）在CDI中的作用，MK2激酶是p38依赖性炎症的关键介质。将培养的肠上皮细胞暴露于艰难梭菌毒素TcdA和TcdB中可导致p38依赖性MK2激活。毒素诱导的IL-8和GRO α释放需要MK2活性。我们发现p38和MK2在其他肌动蛋白破坏剂的作用下被激活，这表明毒素诱导的细胞骨架破坏是激酶依赖性细胞因子反应的触发因素。在艰难梭菌感染的仓鼠和小鼠的肠道中检测到磷酸化的MK2，首次证明该途径在感染动物中被激活。此外，我们发现，在提交艰难梭菌检测的100例患者粪便样本中，pMK2升高与产毒素艰难梭菌的存在相关。综上所述，我们发现MK2激酶可被TcdA和TcdB激活，并调节促炎细胞因子的表达。p38-MK2在受感染动物和人类中的激活表明，这一途径是CDI患者肠道炎症的关键驱动因素。
Clostridium difficile infection (CDI) results in toxin-induced epithelial injury and marked intestinal inflammation. Fecal markers of intestinal inflammation correlate with CDI disease severity, but regulation of the inflammatory response is poorly understood. Previous studies demonstrated that C. difficile toxin TcdA activates p38 kinase in tissue culture cells and mouse ilium, resulting in interleukin-8 (IL-8) release. Here, we investigated the role of phosphorylated mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2 kinase, pMK2), a key mediator of p38-dependent inflammation, in CDI. Exposure of cultured intestinal epithelial cells to the C. difficile toxins TcdA and TcdB resulted in p38-dependent MK2 activation. Toxin-induced IL-8 and GRO alpha release required MK2 activity. We found that p38 and MK2 are activated in response to other actin-disrupting agents, suggesting that toxin-induced cytoskeleton disruption is the trigger for kinase-dependent cytokine response. Phosphorylated MK2 was detected in the intestines of C. difficile-infected hamsters and mice, demonstrating for the first time that the pathway is activated in infected animals. Furthermore, we found that elevated pMK2 correlated with the presence of toxigenic C. difficile among 100 patient stool samples submitted for C. difficile testing. In conclusion, we find that MK2 kinase is activated by TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with CDI.