Interleukin-9 reduces lung fibrosis and type 2 immune polarization induced by 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 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-gamma 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.
Arras
M
M
Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, University Hospital of Mont Godinne, Université Catholique de Louvain, Brussels, Belgium.
Huaux
F
F
Vink
A
A
Delos
M
M
Coutelier
J P
JP
Many
M C
MC
Barbarin
V
V
Renauld
J C
JC
Lison
D
D
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D003460:Crystallization; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006909:Hydroxyproline / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D016906:Interleukin-9 / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000737:chemistry / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012822:Silicon Dioxide / Q000737:chemistry / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D007074:Immunoglobulin G; D016906:Interleukin-9; D011994:Recombinant Proteins; D015847:Interleukin-4; D012822:Silicon Dioxide; D007371:Interferon-gamma; D006909:Hydroxyproline