C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation
C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation
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DOI：
10.1189/jlb.1107783
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发表时间：
2008-04-01
影响因子：
5.5
通讯作者：
Pearlman, Eric
中科院分区：
文献类型：
--
作者：
Adhikary, Gautam;Sun, Yan;Pearlman, Eric
TLR在宿主对细菌和细菌产物的炎症反应中起重要作用，其通过激活导致促炎性和趋化性细胞因子产生的细胞内事件级联。为了确定MAPK在TLR诱导的角膜炎症中的作用，我们用TLR 2配体、三棕榈酰-S-甘油-Cys（Lys）4（Pam 3Cys）或灭活的金黄色葡萄球菌刺激人角膜上皮（HCE）细胞，并检查MAPK表达的时间过程以及MAPK抑制对IkB α降解和CXC趋化因子产生的影响。我们发现S.金黄色葡萄球菌和Pam 3Cys在4小时内刺激JNK、p38 MAPK和ERK磷酸化，阻断JNK而不是p38或ERK磷酸化对IkB α降解和CXC趋化因子产生具有抑制作用。为了确定JNK在体内TLR 2诱导的角膜炎症中是否也是重要的，我们在TLR 2诱导的角膜炎症的小鼠模型中检查了JNK 1（-/-）小鼠和药理学抑制剂，该模型的特征在于中性粒细胞募集到角膜基质和角膜混浊的发展。我们发现，与对照组小鼠相比，JNK 1（-/-）小鼠的角膜炎症明显受损，与载体对照组相比，JNK抑制剂治疗的小鼠角膜炎症明显受损。结合HCE细胞的结果，这些发现表明JNK在TLR 2诱导的角膜炎症中具有重要作用。
TLRs play an important role in the host inflammatory response to bacteria and bacterial products by activating a cascade of intracellular events leading to production of proinflammatory and chemotactic cytokines. To determine the role of MAPKs in TLR-induced corneal inflammation, we stimulated human corneal epithelial (HCE) cells with TLR2 ligands, tripalmitoyl-S-glycero-Cys(Lys) 4 (Pam3Cys) or inactivated Staphylococcus aureus, and examined the time course of expression of MAPKs and the effect of MAPK inhibition on IkB alpha degradation and CXC chemokine production. We found that S. aureus and Pam3Cys stimulate phosphorylation of JNK, p38 MAPK, and ERK within 4 h and that blockade of JNK, but not p38 or ERK phosphorylation, had an inhibitory effect on IkB alpha degradation and CXC chemokine production. To determine if JNK is also important in TLR2- induced corneal inflammation in vivo, we examined JNK1(-/-) mice and pharmacological inhibitors in a murine model of TLR2-induced corneal inflammation which is characterized by neutrophil recruitment to the corneal stroma and development of corneal haze. We found that corneal inflammation was significantly impaired in JNK1(-/-) mice compared with control mice, and in mice treated with the JNK inhibitor compared with vehicle control. Taken together with results from HCE cells, these findings demonstrate that JNK has an essential role in TLR2-induced corneal inflammation.