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

Abstract

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.

IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

“…Exaggerated levels of IL-13 production have been implicated in the pathogenesis of a variety of disorders, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, scleroderma, hepatic fibrosis, and nodular sclerosing Hodgkin's disease (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). The remarkable effects that IL-13 can have in these disorders can be appreciated in studies that highlighted the ability of IL-13 to induce tissue inflammation, cathepsin-and MMP-mediated proteolysis, and TGF-␤1-induced tissue fibrosis (25,32,48).…”

The Role of the Th2 CC Chemokine Ligand CCL17 in Pulmonary Fibrosis

“…Similarly IL-13 has been shown to induce fibrosis by selectively stimulating production and activation of TGF-␤ (15). We have shown that IL-13 promotes bleomycin-induced fibrosis, in part, through the elaboration of CCL6 (9). Neutralization of IL-13 lead to a reduction in fibrosis and macrophage numbers (9).…”

“…Mice were maintained in specific pathogenfree conditions and provided with food and water ad libitum. To induce pulmonary fibrosis, mice were treated with intratracheal bleomycin (Blenoxane, a gift from Bristol Myers, Evansville, IN) (1 U/kg) on day 0 as previously described (9,19,20). Control animals received only sterile saline as previously described (9,19,20).…”

“…We have shown that IL-13 promotes bleomycin-induced fibrosis, in part, through the elaboration of CCL6 (9). Neutralization of IL-13 lead to a reduction in fibrosis and macrophage numbers (9). Similar use of an IL-13 immunotoxin chimeric molecule that antagonizes the effect of IL-13 lead to a reduction in bleomycin-induced pulmonary fibrosis (16).…”

Adenosine in fibrosis

“…The induction of fibrotic changes in the lungs, much as elsewhere, takes place over a substantial period of time and under the influence of a host of profibrotic cytokines, growth factors, and other tissue mediators. One of these recently highlighted is interleukin-13 (IL-13), and trans-genic IL-13 has also been identified to have potent fibro-genic effects in a variety of tissues including both lung and liver [56–59]. Blackburn et al [53] first reported a vast increase in adenosine levels in the lungs of IL-13 trans-genic mice, and this elevation was associated with a sig-nificant suppression of the activity of adenosine deaminase, a major catabolizing enzyme of adenosine.…”