title: Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells.
abstract: We recently proposed a role for the two-pore-domain K(+) (K2P) channel Trek-1 in the regulation of cytokine release from mouse alveolar epithelial cells (AECs) by demonstrating decreased interleukin-6 (IL-6) secretion from Trek-1-deficient cells, but the underlying mechanisms remained unknown. This study was designed to investigate the mechanisms by which Trek-1 decreases IL-6 secretion. We hypothesized that Trek-1 regulates tumor necrosis factor-α (TNF-α)-induced IL-6 release via NF-κB-, p38-, and PKC-dependent pathways. We found that Trek-1 deficiency decreased IL-6 secretion from mouse and human AECs at both transcriptional and translational levels. While NF-κB/p65 phosphorylation was unchanged, p38 phosphorylation was decreased in Trek-1-deficient cells, and pharmacological inhibition of p38 decreased IL-6 secretion in control but not Trek-1-deficient cells. Similarly, pharmacological inhibition of PKC also decreased IL-6 release, and we found decreased phosphorylation of the isoforms PKC/PKDμ (Ser(744/748)), PKCθ, PKCδ, PKCα/βII, and PKCζ/λ, but not PKC/PKDμ (Ser(916)) in Trek-1-deficient AECs. Phosphorylation of PKCθ, a Ca(2+)-independent isoform, was intact in control cells but impaired in Trek-1-deficient cells. Furthermore, TNF-α did not elevate the intracellular Ca(2+) concentration in control or Trek-1-deficient cells, and removal of extracellular Ca(2+) did not impair IL-6 release. In summary, we report the expression of Trek-1 in human AECs and propose that Trek-1 deficiency may alter both IL-6 translation and transcription in AECs without affecting Ca(2+) signaling. The results of this study identify Trek-1 as a new potential target for the development of novel treatment strategies against acute lung injury.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA. aschwing@uthsc.edu
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwingshackl
authors.forename: Bin
authors.initials: B
authors.lastname: Teng
authors.forename: Manik
authors.initials: M
authors.lastname: Ghosh
authors.forename: Keng Gat
authors.initials: KG
authors.lastname: Lim
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Damodaran
authors.initials: D
authors.lastname: Narayanan
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D055371:Acute Lung Injury / Q000503:physiopathology; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D024683:Potassium Channels, Tandem Pore Domain; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C103742:potassium channel protein TREK-1; D011493:Protein Kinase C; D002118:Calcium