IL-37 Attenuates Lung Fibrosis by Inducing Autophagy and Regulating TGF-β1 Production in Mice

• Published in: The Journal of immunology (1950) Vol. 203; no. 8; pp. 2265 - 2275
• Main Authors: Kim, Mi So, Baek, Ae Rin, Lee, June Hyuk, Jang, An Soo, Kim, Do Jin, Chin, Su Sie, Park, Sung Woo
• Format: Journal Article
• Language: English
• Published: United States 15-10-2019
• Subjects: Adult; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal - immunology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Autophagy - drug effects; Autophagy - immunology; Cell Proliferation - drug effects; Cells, Cultured; Female; Humans; Idiopathic Pulmonary Fibrosis - immunology; Idiopathic Pulmonary Fibrosis - pathology; Interleukin-1 - genetics; Interleukin-1 - immunology; Male; Mice; Middle Aged; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - biosynthesis; Transforming Growth Factor beta1 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801515

Idiopathic pulmonary fibrosis (IPF) is a progressive and destructive lung disease with a poor prognosis resulting in a high mortality rate. IL-37 is an anti-inflammatory cytokine that inhibits innate and adaptive immunity by downregulating proinflammatory mediators and pathways. However, the exact role of IL-37 in lung fibrosis is unclear. In this study, we found that the IL-37 protein was expressed in alveolar epithelial cells (AECs) and alveolar macrophages in healthy controls but significantly reduced in patients with IPF. IL-37 significantly inhibited oxidative stress-induced primary mouse AEC death in a dose-dependent manner, and knockdown of IL-37 significantly potentiated human lung cancer-derived AEC (A549 cells) death. IL-37 attenuated constitutive mRNA and protein expression of fibronectin and collagen I in primary human lung fibroblasts. IL-37 inhibited TGF-β1-induced lung fibroblast proliferation and downregulated the TGF-β1 signaling pathway. Moreover, IL-37 enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts. IL-37 significantly decreased inflammation and collagen deposition in bleomycin-exposed mouse lungs, which was reversed by treatment with the autophagy inhibitor 3-methyladenine. Our findings suggested that a decrease in IL-37 may be involved in the progression of IPF and that IL-37 inhibited TGF-β1 signaling and enhancement of autophagy in IPF fibroblasts. Given its antifibrotic activity, IL-37 could be a therapeutic target in fibrotic lung diseases, including IPF.