Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells

Andreas Schwingshackl, Bin Teng, Manik Ghosh, Keng Gat Lim, Gabor Tigyi, Damodaran Narayanan, Jonathan H. Jaggar, Christopher M. Waters

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 (Ser744/748), PKCθ, PKCδ, PKCα/βII, and PKCζ/λ, but not PKC/PKDμ (Ser916) in Trek-1-deficient AECs. Phosphorylation of PKCθ, a Ca2+-independent isoform, was intact in control cells but impaired in Trek-1-deficient cells. Furthermore, TNF-α did not elevate the intracellular Ca2+ concentration in control or Trek-1-deficient cells, and removal of extracellular Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)L276-L286
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume304
Issue number4
DOIs
StatePublished - Feb 15 2013

Fingerprint

Alveolar Epithelial Cells
Potassium Channels
Interleukin-6
Phosphorylation
Protein Isoforms
Tumor Necrosis Factor-alpha
Pharmacology
Acute Lung Injury
Cytokines

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells. / Schwingshackl, Andreas; Teng, Bin; Ghosh, Manik; Lim, Keng Gat; Tigyi, Gabor; Narayanan, Damodaran; Jaggar, Jonathan H.; Waters, Christopher M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 304, No. 4, 15.02.2013, p. L276-L286.

Research output: Contribution to journalArticle

Schwingshackl, Andreas ; Teng, Bin ; Ghosh, Manik ; Lim, Keng Gat ; Tigyi, Gabor ; Narayanan, Damodaran ; Jaggar, Jonathan H. ; Waters, Christopher M. / Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013 ; Vol. 304, No. 4. pp. L276-L286.
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