Am. J. Respir. Cell Mol. Biol., Volume 20, Number 4, April, 1999 561-572

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

François Huaux, Cecile Lardot, Mohammed Arras, Monique Delos, Marie-Christine Many, Jean-Paul Coutelier, Jean-Pierre Buchet, Jean-Christophe Renauld, and Dominique Lison

Industrial Toxicology and Occupational Medicine Unit and Laboratory of Pathology, Hospital of Mont Godinne, Yvair, and Histology Laboratory and Unit of Experimental Medicine, International Institute of Cellular and Molecular Pathology, Faculty of Medicine, Catholic University of Louvain, Louvain, Belgium

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)- and dominant levels of IgG_2a 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.

This article has been cited by other articles:

				T. Sato, T. Shimosato, W. G. Alvord, and D. M. Klinman Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation J. Immunol., June 1, 2008; 180(11): 7648 - 7654. [Abstract] [Full Text] [PDF]

				A. A. Shvedova, J. P. Fabisiak, E. R. Kisin, A. R. Murray, J. R. Roberts, Y. Y. Tyurina, J. M. Antonini, W. H. Feng, C. Kommineni, J. Reynolds, et al. Sequential Exposure to Carbon Nanotubes and Bacteria Enhances Pulmonary Inflammation and Infectivity Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 579 - 590. [Abstract] [Full Text] [PDF]

				L. R. Young, R. Pasula, P. M. Gulleman, G. H. Deutsch, and F. X. McCormack Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 67 - 74. [Abstract] [Full Text] [PDF]

				P. Misson, S. van den Brule, V. Barbarin, D. Lison, and F. Huaux Markers of macrophage differentiation in experimental silicosis J. Leukoc. Biol., November 1, 2004; 76(5): 926 - 932. [Abstract] [Full Text] [PDF]

				L. de Franceschi, A. Baron, A. Scarpa, C. Adrie, A. Janin, S. Barbi, J. Kister, P. Rouyer-Fessard, R. Corrocher, P. Leboulch, et al. Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation Blood, August 1, 2003; 102(3): 1087 - 1096. [Abstract] [Full Text] [PDF]

				F. Huaux, M. Arras, D. Tomasi, V. Barbarin, M. Delos, J.-P. Coutelier, A. Vink, S. H. Phan, J.-C. Renauld, and D. Lison A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis J. Immunol., September 1, 2002; 169(5): 2653 - 2661. [Abstract] [Full Text] [PDF]

				B. Nemery, A. Bast, J. Behr, P.J.A. Borm, S.J. Bourke, Ph. Camus, P. De Vuyst, H.M. Jansen, V.L. Kinnula, D. Lison, et al. Interstitial lung disease induced by exogenous agents: factors governing susceptibility Eur. Respir. J., July 1, 2001; 18(32_suppl): 30S - 42s. [Abstract] [Full Text] [PDF]

				T. Maeyama, K. Kuwano, M. Kawasaki, R. Kunitake, N. Hagimoto, and N. Hara Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12 Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1128 - L1137. [Abstract] [Full Text] [PDF]

				M. Arras, F. Huaux, A. Vink, M. Delos, J.-P. Coutelier, M.-C. Many, V. Barbarin, J.-C. Renauld, and D. Lison Interleukin-9 Reduces Lung Fibrosis and Type 2 Immune Polarization Induced by Silica Particles in a Murine Model Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 368 - 375. [Abstract] [Full Text]

				G. S. Davis, L. M. Pfeiffer, and D. R. Hemenway Interferon-gamma Production by Specific Lung Lymphocyte Phenotypes in Silicosis in Mice Am. J. Respir. Cell Mol. Biol., April 1, 2000; 22(4): 491 - 501. [Abstract] [Full Text]