Lung Fibrosis Induced by Silica Particles in NMRI Mice Is Associated with an Upregulation of the p40 Subunit of Interleukin-12 and Th-2 Manifestations

Abstract

Interleukin (IL)-12 is a cytokine produced principally by activated macrophages which is involved in control of the T-helper 1/T-helper 2 cell (Th1/Th2) polarization of immune responses. To examine its potential involvement in the development of lung fibrosis, we examined the expression (protein, messenger RNA [mRNA]) of IL-12 (p70) and of its subunits (p40 and p35) in lung homogenates, bronchoalveolar lavage fluid (BALF), and bronchoalveolar lavage (BAL) cell cultures in mouse models of resolutive alveolitis (RA) and fibrosing alveolitis (FA) induced by inorganic particles (manganese dioxide [MnO2] and crystalline silica, respectively). The administration of tungsten carbide (WC), which behaved as an innocuous dust for the lung, served as a negative control condition. The FA was specifically accompanied by a Th2-like polarization characterized by high levels of immunoglobulin (Ig)G1 in BALF and by a protracted overproduction of both p40 protein and mRNA, but not by the biologically active form of IL-12 (p70). In the RA model, the p40 response was only transient, and a Th1-like response was reflected by increased levels of interferon (IFN)-gamma and dominant levels of IgG2a in BALF. Taken together, these findings suggest that production of the p40 subunit of IL-12 and Th2 polarization play important roles in lung inflammatory and fibrotic responses to inhaled inorganic particles.

Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

“…Consistent with previous studies (34,36), silica instillation also triggered a significant increase in the level of KC in BAL ( p Ͻ 0.01; Fig. 6).…”

“…As previously described (26), silicosis was induced by instilling 2.5 mg of silica via an intratracheal catheter into the lungs of normal BALB/c mice. The resultant inflammatory response peaked 3 days later, and was characterized by a pulmonary infiltrate dominated by neutrophils and the production of inflammatory cytokines and chemokines (26,34,35). To assess whether treatment with suppressive ODN reduced this inflammation, two doses of suppressive ODN were administered one day before silica installation (this treatment regimen was selected on the basis of successful preliminary experiments).…”

Pulmonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles

“…Although IL-4 expression was unchanged or decreased, Davis and colleagues (12) showed an increased IFN-␥ response in the lung of mice with silicosis, suggesting a Th1-like lymphocyte-mediated immune response. Opposite results showed that in wild-type animals, silica-induced fibrosis was correlated with markers of a Th2-like response such as upregulation of IL-4 levels in lung tissue and an increased immunoglobulin IgG1/IgG2a ratio in BAL (24). In the present study, BALF IgG2a levels (Th1) were not modified after silica or AdIL-10 administration.…”

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

“…IL-12p40 has been found to be produced largely by activated pulmonary macrophages during the fibrotic reaction (23). In this study, we report in the C57BL/6 strain that experimental silicosis is also related with increased IL-12p40 levels, but, in contrast, with a parallel decrease of IL-12p70 content (Fig.…”