IFN-γ Enhances the Cough Reflex Sensitivity via Calcium Influx in Vagal Sensory Neurons

Cough hypersensitivity syndrome is often triggered by a viral infection. The viral infection might trigger cough hypersensitivity via increasing the release of IFN-γ from T lymphocytes in the lung.

To investigate effects of IFN-γ on the vagal sensory neurons and the cough reflex.

Effects of IFN-γ on the cough reflex were investigated in guinea pigs. Cellular immunofluorescence imaging, calcium imaging, and patch clamp techniques were used to study effects of IFN-γ in primary cultured rat vagal sensory neurons.

Intratracheal instillation of IFN-γ enhanced the cough response to citric acid in vivo. IFN-γ significantly increased levels of phosphorylated signal transducer and activator of transcription-1 but not phosphorylated transient receptor potential vanilloid 1 in vitro. Not only did IFN-γ enhance the response of neurons to capsaicin and electric stimulation, but also it directly induced Ca²⁺ influx, membrane depolarization, and action potentials in neurons via the Janus kinase, protein kinase A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid pathways. However, IFN-γ did not elicit Ca²⁺ release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN-γ-induced action potentials were suppressed by Ca²⁺ influx inhibitors, IFN-γ-induced Ca²⁺ influx was not altered by an inhibitor of rapid sodium channels.

The membrane potential in vagal sensory neurons may be depolarized by IFN-γ-induced Ca²⁺ influx. The depolarization of membrane potentials may enhance the cough reflex sensitivity and cause action potentials. IFN-γ may be a new target for treating cough hypersensitivity syndrome and postviral cough.