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Published ahead of print on February 19, 2004, doi:10.1165/rcmb.2003-0299OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 78-85, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0299OC

Original Article

Characterization of the Effect of Interleukin-10 on Silica-Induced Lung Fibrosis in Mice

Virginie Barbarin, Mohammed Arras, Pierre Misson, Monique Delos, Bridget McGarry, Sem H. Phan, Dominique Lison and François Huaux

Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, and Laboratory of Pathology, University Hospital of Mont Godinne, Yvoir, Université Catholique de Louvain, Brussels, Belgium; and Department of Pathology, University of Michigan, Ann Arbor, Michigan

Address correspondence to: Francois Huaux, Unit of Industrial Toxicology and Occupational Medicine, Faculty of Medicine, Université Catholique de Louvain, 30.54 Clos Chapelle-aux-Champs, B-1200 Brussels, Belgium. E-mail: huaux{at}toxi.ucl.ac.be

We previously described a reduction of silica–induced lung fibrosis in interleukin-10–deficient mice (IL-10–/–) (Huaux and colleagues; Am. J. Respir. Cell Mol. Biol. 1998;18:51–59). In the present study, we further dissect the exact functions of IL-10 in experimental silicosis. The reduced lung fibrotic response to silica in IL-10–/– mice was accompanied by a marked recruitment of TH1 CD4+ lymphocytes. However, treatment with anti-CD4 antibodies reduced silica–induced lung fibrosis in both IL-10–/– and IL-10+/+ mice, suggesting that this T cell population actually contributes to the extension of the fibrotic lesions in a manner that is independent of IL-10. In IL-10–/– mice, silica–induced lung production of the profibrotic mediator transforming growth factor (TGF)-ß1 and the antifibrotic eicosanoid PGE2 were reduced and increased, respectively, relative to that in IL-10+/+ mice. In addition, in vitro experiments indicated that recombinant IL-10 upregulated TGF-ß1 expression in alveolar macrophages while in contrast it downregulated PGE2 production and cyclooxygenase-2 expression in both lung fibroblasts and macrophages. Thus the net profibrotic activity of IL-10 in vivo appears to be mediated by its ability to stimulate the expression of the profibrotic cytokine TGF-ß1 while suppressing the expression of cyclooxygenase-2 and thus production of the antifibrotic eicosanoid PGE2. These effects appear to be independent of the enhanced lung CD4+ T-lymphocytosis observed in IL-10–deficient mice.

Abbreviations: alveolar macrophages, AM • {alpha}-smooth muscle action, {alpha}-SMA • bronchoalveolar lavage, BAL • cyclooxygenase-2, COX-2 • interleukin, IL • interleukin-10–deficient mice, KO IL-10, IL-10–/– • IL-10–sufficient mice, IL-10+/+ • natural killer, NK • real-time reverse transcriptase polymerase chain reaction, RT-PCR • signal transducer and activator of transcription, STAT • transforming growth factor-ß1, TGF-ß1




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