American Journal of Translational Research | |
Regulation of Monocyte Chemotactic Protein-1 secretion by the Two-Pore-Domain Potassium (K2P) channel TREK-1 in human alveolar epithelial cells | |
Andreas Schwingshackl1  | |
关键词: TREK-1; MCP-1; TNF-α; chemokine; epithelium; acute lung injury; | |
DOI : | |
学科分类:医学(综合) | |
来源: e-Century Publishing Corporation | |
【 摘 要 】
We recently proposed a role for the 2-pore-domain K+ (K2P) channel TREK-1 in the regulation of cytokine release from alveolar epithelial cells (AECs) by demonstrating decreased IL-6 secretion from TREK-1 deficient cells, but the effects of altered TREK-1 expression on other inflammatory mediators remain poorly understood. We now examined the role of TREK-1 in TNF-α-induced MCP-1 release from human A549 cells. We hypothesized that TREK-1 regulates TNF-α-induced MCP-1 secretion via c-Jun N-terminal kinases (JNK)- and protein kinase-C (PKC)-dependent pathways. In contrast to IL-6 secretion, we found that TREK-1 deficiency resulted in increased MCP-1 production and secretion, although baseline MCP-1 gene expression was unchanged in TREK-1 deficient cells. In contrast to TREK-1 deficient AECs, overexpression of MCP-1 had no effect on MCP-1 secretion. Phosphorylation of JNK1/2/3 was increased in TREK-1 deficient cells upon TNF-α stimulation, but pharmacological inhibition of JNK1/2/3 decreased MCP-1 release from both control and TREK-1 deficient cells. Similarly, pharmacological inhibition of PKC decreased MCP-1 secretion from control and TREK-1 deficient cells, suggesting that alterations in JNK and PKC signaling pathways were unlikely the cause for the increased MCP-1 secretion from TREK-1 deficient cells. Furthermore, MCP-1 secretion from control and TREK-1 deficient cells was independent of extracellular Ca2+ but sensitive to inhibition of intracellular Ca2+ reuptake mechanisms. In summary, we report for the first time that TREK-1 deficiency in human AECs resulted in increased MCP-1 production and secretion, and this effect appeared unrelated to alterations in JNK-, PKC- or Ca2+-mediated signaling pathways in TREK-1 deficient cells.
【 授权许可】
CC BY-NC
【 预 览 】
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