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Interaction of IL-13 and C10 in the Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis

Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, California; and Division of Pulmonary and Critical Care Medicine, Yale University, New Haven, Connecticut

Address correspondence to: Dr. Michael P. Keane, UCLA, Department of Medicine, Division of Pulmonary and Critical Care Medicine, 900 Veteran Ave, 14-154 Warren Hall, Los Angeles, CA 90095-1922. E-mail: mpkeane{at}mednet.ucla.edu

The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. Although interleukin (IL)-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that support fibroproliferation, it is also a potent inducer of a novel CC chemokine, C10, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. In this study we demonstrate that IL-13 and C10 are elevated in the pathogenesis of bleomycin-induced pulmonary fibrosis. Neutralization of IL-13, but not IL-4, attenuated bleomycin-induced pulmonary fibrosis and levels of C10, suggesting that IL-13 has an important role in the development of pulmonary fibrosis. IL-13 is a potent inducer of C10 in vivo, and neutralization of C10 attenuated bleomycin-induced pulmonary fibrosis and intrapulmonary macrophage numbers. This suggests that IL-13 has a role in the development of pulmonary fibrosis that is independent of its direct effect on fibroblasts and is evidence for an interaction between Th2 cytokines and specific CC chemokines.

Abbreviations: bronchoalveolar lavage, BAL • BAL fluid, BALF • enzyme-linked immunosorbent assay, ELISA • interferon-, IFN- • interleukin, IL • idiopathic pulmonary fibrosis, IPF • macrophage inflammatory protein, MIP • matrix metalloproteinase, MMP • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • transforming growth factor, TGF • tissue inhibitor of metalloproteinase, TIMP • tumor necrosis factor, TNF

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