title: Regulation of Monocyte Chemotactic Protein-1 secretion by the Two-Pore-Domain Potassium (K2P) channel TREK-1 in human alveolar epithelial cells.
abstract: 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 Ca(2+) but sensitive to inhibition of intracellular Ca(2+) 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 Ca(2+)-mediated signaling pathways in TREK-1 deficient cells.
authors: Department of Pediatrics, University of Tennessee Health Science Center Memphis, TN 38103, USA ; Department of Physiology, University of Tennessee Health Science Center Memphis, TN 38103, USA.
authors: Andreas
authors: A
authors: Schwingshackl
authors: Bin
authors: B
authors: Teng
authors: Manik
authors: M
authors: Ghosh
authors: Christopher M
authors: CM
authors: Waters
keywords: MCP-1; TNF-α; TREK-1; acute lung injury; chemokine; epithelium
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