Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP
Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP
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DOI：
10.1111/bph.13373
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发表时间：
2016-01-01
影响因子：
7.3
通讯作者：
Horiuchi, Hisanori
中科院分区：
文献类型：
--
作者：
Shishikura, Kyosuke;Horiuchi, Takahiro;Horiuchi, Hisanori
背景和目的中性粒细胞在受到刺激后，释放出其核内的内含物，称为中性粒细胞胞外陷阱（NETs），其中含有未折叠的染色质和溶酶体酶。NET已被证明在宿主防御中起关键作用，尽管PGE（2）（一种在炎症组织中产生的生物活性物质）在NET形成中的作用尚不清楚。和cAMP的调节剂-PKA通路对NETs形成的影响在离体中性粒细胞和新建立的小鼠模型中进行了体外研究。Key ResultsPGE（2）抑制PMA-通过EP 2和EP 4 Gs偶联受体诱导体外NET形成。与细胞可渗透的cAMP类似物、二丁酰cAMP或cAMP降解酶PDE的各种抑制剂一起孵育也抑制了NET的形成。在这里建立的测定中，其中琼脂糖凝胶是s.c.结论PGE（2）通过产生cAMP抑制NET的形成。这些发现将有助于开发NETosis相关疾病的新疗法。
Background and PurposeUpon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE(2), a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear.Experimental ApproachThe effects of PGE(2), agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model.Key ResultsPGE(2) inhibited PMA-induced NET formation in vitro through EP2 and EP4 Gs-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP2 receptor agonist.Conclusions and ImplicationsPGE(2) inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis-related diseases.