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

Interleukin (IL)-12 is a cytokine produced principally by activated macroph ages which is involved in control of the T-helper 1/T-helper 2 cell (Th1/Th 2) polarization of immune responses. To examine its potential involvement i n the development of lung fibrosis, we examined the expression (protein, me ssenger RNA [mRNA]) of IL-12 (p70) and of its subunits (p40 and p35) in lun g homogenates, bronchoalveolar lavage fluid (BALF), and bronchoalveolar lav age (BAL) cell cultures in mouse models of resolutive alveolitis (RA) and f ibrosing alveolitis (FA) induced by inorganic particles (manganese dioxide [MnO2] and crystalline silica, respectively). The administration of tungste n 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)G(1) i n 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 p 40 response was only transient, and a Th1-like response was reflected by in creased levels of interferon (IFN)-gamma and dominant levels of IgG(2a) in BALF. Taken together, these findings suggest that production of the p40 sub unit of IL-12 and Th2 polarization play important roles in lung inflammator y and fibrotic responses to inhaled inorganic particles.