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Novel inflammatory mechanisms in the regulation of airway hyperresponsiveness: regulation of airway smooth muscle Kv7 channel expression by REST.
Author(s) -
Brueggemann Lyubov I.,
Zhang Chonyu,
Kakad Priyanka P.,
Cribbs Leanne L.,
Byron Kenneth L.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.726.5
Subject(s) - ovalbumin , endocrinology , medicine , rest (music) , inflammation , guinea pig , potassium channel , biology , immunology , immune system
Inflammation contributes to airway hyperresponsiveness (AHR) in asthma, but the cellular mechanisms by which this occurs are not well understood. In previous research, inflammatory mediators were found to upregulate repressor element 1‐silencing transcription factor (REST) in neurons, and consequently, REST mediated transcriptional suppression of neuronal KCNQ genes, which was associated with decreased M‐current density and increased neuronal excitability. Functional binding sites for REST have been identified in both KCNQ4 and KCNQ5 genes which encode Kv7.4 and Kv7.5 potassium channels expressed in airway smooth muscle cells (ASMCs). We found that Kv7 currents and KCNQ gene expression were both decreased in ovalbumin‐(OA‐) sensitized guinea pigs (a model for allergic asthma) relative to saline‐treated control guinea pigs. Although REST has not been reported to be expressed in ASMCs, we found that it is expressed and that REST protein levels are significantly higher in the nuclei of ASMCs from sensitized guinea pigs relative to saline control guinea pigs. Furthermore, serum from the OA‐sensitized animals, but not from control animals, increased nuclear REST immunostaining in ASMCs of control animals. In previous research, serum from sensitized guinea pigs or from asthmatic humans was shown to induce features of AHR in ASMCs, and features of AHR could also be induced by treating human ASMCs with purified inflammatory mediators, including IL‐4 and IL‐13. We exposed strips of human trachealis tissue to IL‐13 overnight and observed a significant increase in nuclear REST expression in ASMCs, supporting a specific role for IL‐13 and providing evidence that this pathway is active in human ASMCs. These findings provide new evidence for an inflammatory mechanism that might account for airway smooth muscle hyper‐excitability in asthma. Support or Funding Information The project described was supported by Award Number I01BX007080 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development.