Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 368-375

Interleukin-9 Reduces Lung Fibrosis and Type 2 Immune Polarization Induced by Silica Particles in a Murine Model

Mohammed Arras, François Huaux, Anne Vink, Monique Delos, Jean-Paul Coutelier, Marie-Christine Many, Virginie Barbarin, Jean-Christophe Renauld, and Dominique Lison

Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine; Laboratory of Pathology, University Hospital of Mont Godinne; Laboratory of Histology, Faculty of Medicine; and Unit of Experimental Medicine and Ludwig Institute for Cancer Research, Faculty of Medicine, Université Catholique de Louvain, Brussels, Belgium

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 lung fibrosis induced by crystalline silica particles. Therefore, we compared the response to silica (1 and 5 mg/animal, intratracheally) in transgenic mice that constitutively express high levels of IL-9 (Tg5) and their wild-type counterparts (FVB). At 2 and 4 mo after treatment with silica, histologic examination and measurement of lung hydroxyproline content showed that the severity of fibrosis was significantly less important in Tg5 mice than in their wild-type counterparts. Intraperitoneal injection of IL-9 in C57BL/6 mice also reduced the amplitude of silica-induced lung fibrosis. The reduction 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 correlated with markers of a T helper 2-like response such as upregulation of IL-4 levels in lung tissue and an increased immunoglobulin (Ig) G1/IgG2a ratio in BAL. Immunohistochemical studies demonstrated that the upregulation of IL-4 associated with the development of fibrosis was mainly localized in inflammatory alveolar macrophages. In transgenic mice, the level of IL-4 in lung homogenates was not significantly affected by silica treatment, and a reduced IgG1/IgG2a ratio was observed upon treatment with silica. The levels of interferon- were significantly decreased after silica treatment in both strains. Together, these observations point to an antifibrotic effect of IL-9 in pulmonary fibrosis associated with a limitation of the type 2 polarization which accompanies lung fibrosis.

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