Pulmonary IFN-gamma Causes Lymphocytic Inflammation and Cough Hypersensitivity by Increasing the Number of IFN-gamma-Secreting T Lymphocytes

Purpose: Respiratory viral infection increases the number of lung-resident T lymphocytes, which enhance cough sensitivity by producing interferon-gamma (IFN-gamma). It is poorly understood why IFN-gamma-secreting T lymphocytes persist for a long time when the respiratory viruses have been removed.Methods: Repeated pulmonary administration of IFN-gamma and intraperitoneal injection with different inhibitors were used to study the effects of pulmonary IFN-gamma in mice and guinea pigs.Results: IFN-gamma administration caused the increasing of IFN-gamma-secreting T lymphocytes in both lung and blood, followed by the elevated physiological level of IFN-gamma in the lung, the airway inflammation and the airway epithelial damage. IFN-gamma administration also enhanced the cough sensitivity of guinea pigs. IFN-gamma activated the STAT1 and extracellular signal -regulated kinase (ERK) pathways in lung tissues, released IFN-gamma-inducible protein 10 (IP-10), and resulted in F-actin accumulation in lung-resident lymphocytes. The CXC chemokine receptor 3 (CXCR3) inhibitor potently suppressed all the IFN-gamma-induced inflammatory changes. The STAT1 inhibitor mitigated IFN-gamma-secreting T lymphocytes infiltration by inhibiting T lymphocytes proliferation. F-actin accumulation and the ERK1/2 pathway contributed to pulmonary IFN-gamma-induced augmentation of the airway inflammation and increasing of IFN-gamma-secreting T lymphocytes in blood.Conclusions: High physiological levels of IFN-gamma in the lung may cause pulmonary lymphocytic inflammation and cough hypersensitivity by increasing the number of IFN-gamma- secreting T lymphocytes through the IP-10 and CXCR3 pathways.