Intrapulmonary IFN-γ instillation causes chronic lymphocytic inflammation in the spleen and lung through the CXCR3 pathway

Some patients with chronic refractory cough have high levels of pulmonary IFN-γ and IFN-γ-producing T lymphocytes. Pulmonary IFN-γ administration causes acute airway lymphocytic inflammation and cough hypersensitivity by increasing the number of pulmonary IFN-γ-producing T lymphocytes, but these lymphocytes may be recruited from other organs. Intraperitoneal IFN-γ injection can increase the spleen weight of mice. It remains elusive whether pulmonary IFN-γ can induce chronic airway lymphocytic inflammation and cough hypersensitivity by stimulating the proliferation of IFN-γ -producing T lymphocytes in the spleen. Here, we found that pulmonary IFN-γ administration induced chronic airway inflammation and chronic cough hypersensitivity with an increased number of IFN-γ-producing T lymphocytes in the spleen, blood and lung. Pulmonary IFN-γ administration also increased 1) the proliferation of spleen lymphocytes in vivo and 2) the IP-10 level and CXCR3+ T lymphocyte numbers in the spleen and lung of mice. IP-10 could promote the proliferation of spleen lymphocytes in vitro but not blood lymphocytes or lung-resident lymphocytes. AMG487, a potent inhibitor of binding between IP-10 and CXCR3, could block pulmonary IFN-γ instillation-induced chronic airway lymphocytic inflammation and the proliferation of IFN-γ-producing T lymphocytes in mouse spleens. In conclusion, intrapulmonary IFN-γ instillation may induce the proliferation of splenic IFN-γ-producing T lymphocytes through IP-10 and the CXCR3 pathway. The IFN-γ-producing T lymphocytes in blood, partly released from the mouse spleen, may be partly attracted to the lung by pulmonary IP-10 through the CXCR3 pathway. IFN-γ-producing T lymphocytes and IFN-γ in the lung may cause chronic airway lymphocytic inflammation and chronic cough hypersensitivity.