A profibrotic function of IL-12p40 in experimental pulmonary fibrosis.
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-gamma/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.
Huaux
Francois
F
Units of Industrial Toxicology and Occupational Medicine, Faculty of Medicine, Brussels, Belgium. huaux@toxi.ucl.ac.be
Arras
Mohammed
M
Tomasi
David
D
Barbarin
Virginie
V
Delos
Monique
M
Coutelier
Jean-Paul
JP
Vink
Anne
A
Phan
Sem H
SH
Renauld
Jean-Christophe
JC
Lison
Dominique
D
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000009:adverse effects / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D007442:Intubation, Intratracheal; D008168:Lung / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012822:Silicon Dioxide / Q000633:toxicity; D012829:Silicosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D011994:Recombinant Proteins; D018664:Interleukin-12; D012822:Silicon Dioxide