Interleukin-9 reduces lung fibrosis and type 2 immune polarization inducedby silica particles in a murine model

We examined the effect of interleukin (IL)-9, a cytokine active on B and T lymphocytes and associated with bronchial asthma, on the development of lun g fibrosis induced by crystalline silica particles. Therefore, we compared the response to silica (1 and 5 mg/animal, intratracheally) in transgenic m ice that constitutively express high levels of IL-9 (Tg5) and their wild-ty pe counterparts (FVB). At 2 and 4 mo after treatment with silica, histologi c: examination and measurement of lung hydroxyproline content showed that t he severity of fibrosis was significantly less important in Tg5 mice than i n their wild-type counterparts. Intraperitoneal injection of IL-9 in C57BL/ 6 mice also reduced the amplitude of silica-induced lung fibrosis. The redu ction of lung fibrosis by IL-9 was associated with a significant expansion of the B-lymphocyte population, both in bronchoalveolar lavage (BAL) and in the pulmonary parenchyma. In wild-type animals, silica-induced fibrosis co rrelated with markers of a T helper 2-like response such as upregulation of IL-4 levels in lung tissue and an increased immunoglobulin tig) G1/lgG2a r atio in BAL. Immunohistochemical studies demonstrated that the upregulation of IL-4 associated with the development of fibrosis was mainly localized i n inflammatory alveolar macrophages. In transgenic mice, the level of IL-4 in lung homogenates was not significantly affected by silica treatment, and a reduced lgG1/lgG2a ratio was observed upon treatment with silica. The le vels of interferon-gamma were significantly decreased after silica treatmen t in both strains. Together, these observations point to an antifibrotic ef fect of IL-9 in pulmonary fibrosis associated with a limitation of the type 2 polarization which accompanies lung fibrosis.