Neutralization of IL-18 by IL-18 binding protein ameliorates bleomycin-induced pulmonary fibrosis via inhibition of epithelial-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a fatal parenchymal lung disease with limited effective therapies. Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine, which acts in both acquired and innate immunity. We have previously reported that IL-18 play an important role in lipopolysaccharide-induced acute lung injury in mice. Persistent inflammation often drives fibrotic progression in the bleomycin (BLM) injury model. However, the role of IL-18 in pulmonary fibrosis (PF) is still unknown. IL-18 binding protein (IL-18BP) is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to investigate the effects of IL-18BP on BLM-induced PF. In the present study, we found that IL-18 was upregulated in lungs of BLM-injured mice. Neutralization of IL-18 by IL-18BP improved the survival rate and ameliorated BLM-induced PF in mice, which was associated with attenuated pathological changes, reduced collagen deposition, and decreased content of transforming growth factor-β1 (TGF-β1). We further demonstrated that IL-18BP treatment suppressed the BLM-induced epithelial mesenchymal transition (EMT), characterized by decreased α-smooth muscle actin (α-SMA) and increased E-cadherin (E-cad) in vivo. In addition, we provided in vitro evidence demonstrating that IL-18 promoted EMT through upregulation of Snail-1 in A549 cells. In conclusion, our findings raise the possibility that the increase of IL-18 is involved in the development of BLM-induced PF through modulating EMT in a Snail-1-dependent manner. IL-18BP may be a worthwhile candidate option for PF therapy.