Department of Chemistry, University of Akron, Akron, Ohio, United States of America.
PLoS One. 2013 Aug 15;8(8):e71536. doi: 10.1371/journal.pone.0071536. eCollection 2013.
Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT1R and CysLT2R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT1R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT1R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1β generation by cys-LTs. Interestingly, cys-LTs activated both PKCα and PKCε isoforms in MC. However, knockdown of PKCα augmented cys-LT mediated calcium flux, while knockdown of PKCε attenuated cys-LT induced c-fos expression and MIP1β generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT1R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
半胱氨酰白三烯（cys-LTs）是一组脂质介质，具有强烈的支气管收缩作用，是血管渗漏的强大诱导剂，也是气道高反应性的增强剂。cys-LTs 在哮喘中起重要作用，并在肥大细胞（MCs）中合成和激活。cys-LTs 通过两种已知的 GPCR（CysLT1R 和 CysLT2R）传递其作用。尽管蛋白激酶 C（PKC）同工型参与了 CysLT1R 功能的调节，但 PKC 在 cys-LT 依赖性 MC 炎症信号中的作用以及特定同工型在 MC 功能中的参与尚不清楚。在这里，我们表明 PKC 抑制通过 MC 中的 CysLT1R 增强了 LTD4 和 LTE4 诱导的钙内流。相比之下，PKC 的抑制抑制了 c-fos 的表达以及 cys-LTs 引起的 MIP1β 的产生。有趣的是，cys-LTs 在 MC 中激活了 PKCα 和 PKCε 同工型。然而，PKCα 的敲低增强了 cys-LT 介导的钙通量，而 PKCε 的敲低减弱了 cys-LT 诱导的 c-fos 表达和 MIP1β 的产生。总之，这些结果首次表明，MC 中 CysLT1R 下游的 cys-LT 信号通过两种不同的 PKC 进行差异调节，这两种 PKC 调节了在过敏反应和哮喘病理中具有重要病理生物学意义的炎症信号。
