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

RATIONALE

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.

OBJECTIVES

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

METHODS

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.

MEASUREMENTS AND MAIN RESULTS

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 Ca 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 Ca release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN-γ-induced action potentials were suppressed by Ca influx inhibitors, IFN-γ-induced Ca influx was not altered by an inhibitor of rapid sodium channels.

CONCLUSIONS

The membrane potential in vagal sensory neurons may be depolarized by IFN-γ-induced Ca 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.