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 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.
Huaux
F
F
Industrial Toxicology and Occupational Medicine Unit and Laboratory of Pathology, Hospital of Mont Godinne, Yvair. huaux@toxi.ucl.ac.be
Lardot
C
C
Arras
M
M
Delos
M
M
Many
M C
MC
Coutelier
J P
JP
Buchet
J P
JP
Renauld
J C
JC
Lison
D
D
D000818:Animals; D000917:Antibody Formation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D046911:Macromolecular Substances; D017895:Manganese Compounds; D051379:Mice; D008815:Mice, Inbred Strains; D010087:Oxides; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012822:Silicon Dioxide; D018418:Th2 Cells / Q000276:immunology*; D014158:Transcription, Genetic; D017973:Tungsten Compounds
D007074:Immunoglobulin G; D046911:Macromolecular Substances; D017895:Manganese Compounds; D010087:Oxides; D012333:RNA, Messenger; D017973:Tungsten Compounds; C002802:tungsten carbide; D018664:Interleukin-12; D012822:Silicon Dioxide; C016552:manganese dioxide