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Units of
* Industrial Toxicology and Occupational Medicine and
Experimental Medicine and Ludwig Institute for Cancer Research, Faculty of Medicine, Brussels, Belgium;
Laboratory of Pathology, University Hospital of Mont Godinne, Yvoir, Belgium; Université Catholique de Louvain, Brussels, Belgium; and
Department of Pathology, University of Michigan, Ann Arbor, MI 48109
The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form
IL-12p70, is secreted during the development of silica-induced lung
fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to
the lung inflammatory and fibrotic processes, we compared the pulmonary
responses with silica particles of IL-12p35-deficient mice
(IL-12p35-/-, able to produce IL-12p40) and
IL-12p40-deficient mice (IL-12p40-/-).
IL-12p35-/- and IL-12p40-/- animals
developed strikingly contrasting responses to silica in comparison with
wild-type C57BL/6 mice. Although the IL-12p40-/- mice
exhibited limited inflammatory and fibrotic reactions, the
IL-12p35-/- mice presented a robust and well-developed
pulmonary inflammation and fibrosis. Furthermore, the silica-induced
increase in lung IL-12p40 content was significantly higher in
IL-12p35-/- mice than in wild-type controls, and was
associated with extensive lung fibrosis and pulmonary macrophage
infiltration. The contrasting responses observed between these two
IL-12 subunit-deficient murine strains were not accompanied by a strict
type 1 or type 2 polarization as estimated by the measurements of lung
IFN-
/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I
collagen expression, as well as myofibroblast differentiation of
purified pulmonary fibroblasts were not affected by treatment with
exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored
the impaired pulmonary fibrotic response and macrophage accumulation in
silica-treated IL-12p40-/- mice, and also promoted
fibrosis and macrophage influx in wild-type mice. Together, our data
suggest that IL-12p40 plays an important role in silica-induced
pulmonary inflammation and fibrosis, possibly by exacerbating
macrophage recruitment.
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