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Interleukin-37 Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice

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Abstract

Pulmonary fibrosis is a disease with chronic inflammation and excessive collagen deposition for which there is no effective treatments. Interleukin (IL)-37 is a newly identified anti-inflammatory cytokine but its role in pulmonary fibrosis remains unclear. In this study, we investigated the effect of IL-37 on bleomycin-induced pulmonary fibrosis in mice. A lentivirus expressing IL-37 was administered intranasally to bleomycin-induced C57BL/6 mice. We found that IL-37 improved the survival of mice and reduced the body weight loss of mice caused by bleomycin. Furthermore, IL-37 significantly attenuated pulmonary inflammatory infiltration and collagen deposition and decreased the hydroxyproline content in bleomycin-treated mice. Finally, IL-37 treatment inhibited the expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α, but increased the expression of interferon-γ in lung tissues from bleomycin-challenged mice. Taken together, these results suggest that in vivo expression of IL-37 is useful in preventing pulmonary fibrosis induced by bleomycin and provides a possible therapeutic approach to pulmonary fibrosis diseases.

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References

  1. American Thoracic Society. 2000. Idiopathic pulmonary fibrosis: Diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). American Journal of Respiratory and Critical Care Medicine 161 (2 Pt 1): 646–664.

    Google Scholar 

  2. Ashcroft, T., J.M. Simpson, and V. Timbrell. 1988. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. Journal of Clinical Pathology 41 (4): 467–470.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ballak, D.B., J.A. van Diepen, A.R. Moschen, H.J. Jansen, A. Hijmans, G.J. Groenhof, F. Leenders, P. Bufler, M.V. Boekschoten, M. Müller, S. Kersten, S. Li, S.H. Kim, H. Eini, E.C. Lewis, L.A.B. Joosten, H. Tilg, M.G. Netea, C.J. Tack, C.A. Dinarello, and R. Stienstra. 2014. IL-37 protects against obesity-induced inflammation and insulin resistance. Nature Communications 5: 4711.

    Article  PubMed  CAS  Google Scholar 

  4. Borzone, G., R. Moreno, R. Urrea, M. Meneses, M. Oyarzun, and C. Lisboa. 2001. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 163 (7): 1648–1653.

    Article  PubMed  CAS  Google Scholar 

  5. Car, B.D., F. Meloni, M. Luisetti, G. Semenzato, G. Gialdroni-Grassi, and A. Walz. 1994. Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. American Journal of Respiratory and Critical Care Medicine 149 (3 Pt 1): 655–659.

    Article  PubMed  CAS  Google Scholar 

  6. Chen, E.S., B.M. Greenlee, M. Wills-Karp, and D.R. Moller. 2001. Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin. American Journal of Respiratory Cell and Molecular Biology 24 (5): 545–555.

    Article  PubMed  CAS  Google Scholar 

  7. Diaz, K.T., S. Skaria, K. Harris, M. Solomita, S. Lau, K. Bauer, G.C. Smaldone, and R. Condos. 2012. Delivery and safety of inhaled interferon-gamma in idiopathic pulmonary fibrosis. Journal of Aerosol Medicine and Pulmonary Drug Delivery 25 (2): 79–87.

    Article  PubMed  CAS  Google Scholar 

  8. Gharaee-Kermani, M., E.M. Denholm, and S.H. Phan. 1996. Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. The Journal of Biological Chemistry 271 (30): 17779–17784.

    Article  PubMed  CAS  Google Scholar 

  9. Habiel, D.M., and C. Hogaboam. 2014. Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis. Frontiers in Pharmacology 5: 2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Henderson, W.R., Jr., E.Y. Chi, X. Ye, C. Nguyen, Y.T. Tien, B. Zhou, Z. Borok, D.A. Knight, and M. Kahn. 2010. Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America 107 (32): 14309–14314.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jankov, R.P., X. Luo, P. Demin, R. Aslam, V. Hannam, A.K. Tanswell, and C.R. Pace-Asciak. 2002. Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse. The Journal of Pharmacology and Experimental Therapeutics 301 (2): 435–440.

    Article  PubMed  CAS  Google Scholar 

  12. Jiang, D., J. Liang, J. Hodge, B. Lu, Z. Zhu, S. Yu, J. Fan, Y. Gao, Z. Yin, R. Homer, C. Gerard, and P.W. Noble. 2004. Regulation of pulmonary fibrosis by chemokine receptor CXCR3. The Journal of Clinical Investigation 114 (2): 291–299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kumar, S., P.C. McDonnell, R. Lehr, L. Tierney, M.N. Tzimas, D.E. Griswold, E.A. Capper, R. Tal-Singer, G.I. Wells, M.L. Doyle, and P.R. Young. 2000. Identification and initial characterization of four novel members of the interleukin-1 family. The Journal of Biological Chemistry 275 (14): 10308–10314.

    Article  PubMed  CAS  Google Scholar 

  14. Le, T.T., H. Karmouty-Quintana, E. Melicoff, T. Weng, N.Y. Chen, M. Pedroza, Y. Zhou, et al. 2014. Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis. Journal of Immunology 193 (7): 3755–3768.

    Article  CAS  Google Scholar 

  15. Luo, Y., X. Cai, S. Liu, S. Wang, C.A. Nold-Petry, M.F. Nold, P. Bufler, D. Norris, C.A. Dinarello, and M. Fujita. 2014. Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 111 (42): 15178–15183.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Manoury, B., S. Nenan, O. Leclerc, I. Guenon, E. Boichot, J.M. Planquois, C.P. Bertrand, and V. Lagente. 2005. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respiratory Research 6: 11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Manoury, B., S. Nenan, I. Guenon, E. Boichot, J.M. Planquois, C.P. Bertrand, and V. Lagente. 2006. Macrophage metalloelastase (MMP-12) deficiency does not alter bleomycin-induced pulmonary fibrosis in mice. Journal of Inflammation (Lond) 3: 2.

    Article  CAS  Google Scholar 

  18. McNamee, E.N., J.C. Masterson, P. Jedlicka, M. McManus, A. Grenz, C.B. Collins, M.F. Nold, C. Nold-Petry, P. Bufler, C.A. Dinarello, and J. Rivera-Nieves. 2011. Interleukin 37 expression protects mice from colitis. Proceedings of the National Academy of Sciences of the United States of America 108 (40): 16711–16716.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Monnier, J., and B.A. Zabel. 2014. Anti-asialo GM1 NK cell depleting antibody does not alter the development of bleomycin induced pulmonary fibrosis. PLoS One 9 (6): e99350.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Moore, B.B., R. Paine 3rd, P.J. Christensen, T.A. Moore, S. Sitterding, R. Ngan, C.A. Wilke, W.A. Kuziel, and G.B. Toews. 2001. Protection from pulmonary fibrosis in the absence of CCR2 signaling. Journal of Immunology 167 (8): 4368–4377.

    Article  CAS  Google Scholar 

  21. Niu, C.H., Y. Wang, J.D. Liu, J.L. Wang, and J.H. Xiao. 2013. Protective effects of neferine on amiodarone-induced pulmonary fibrosis in mice. European Journal of Pharmacology 714 (1–3): 112–119.

    Article  PubMed  CAS  Google Scholar 

  22. Nold, M.F., C.A. Nold-Petry, J.A. Zepp, B.E. Palmer, P. Bufler, and C.A. Dinarello. 2010. IL-37 is a fundamental inhibitor of innate immunity. Nature Immunology 11 (11): 1014–1022.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. O’Connell, O.J., M.P. Kennedy, and M.T. Henry. 2011. Idiopathic pulmonary fibrosis: Treatment update. Advances in Therapy 28 (11): 986–999.

    Article  PubMed  CAS  Google Scholar 

  24. Pantelidis, P., G.C. Fanning, A.U. Wells, K.I. Welsh, and R.M. Du Bois. 2001. Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 163 (6): 1432–1436.

    Article  PubMed  CAS  Google Scholar 

  25. Patel, F.J., D.T. Volkmann, G.W. Taylor, M.A. Hansson, J.F. Anderson, Y. Zhou, L.M. Scoazec, C.V. Hartford, and D.L. Hainz. 2014. IL-37 reduces inflammatory response after cerebral ischemia and reperfusion injury through down-regulation of pro-inflammatory cytokines. Cytokine 69 (2): 234–239.

    Article  PubMed  CAS  Google Scholar 

  26. Piguet, P.F., M.A. Collart, G.E. Grau, Y. Kapanci, and P. Vassalli. 1989. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. The Journal of Experimental Medicine 170 (3): 655–663.

    Article  PubMed  CAS  Google Scholar 

  27. Piguet, P.F., M.A. Collart, G.E. Grau, A.P. Sappino, and P. Vassalli. 1990. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature 344 (6263): 245–247.

    Article  PubMed  CAS  Google Scholar 

  28. Saito, F., S. Tasaka, K. Inoue, K. Miyamoto, Y. Nakano, Y. Ogawa, W. Yamada, Y. Shiraishi, N. Hasegawa, S. Fujishima, H. Takano, and A. Ishizaka. 2008. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. American Journal of Respiratory Cell and Molecular Biology 38 (5): 566–571.

    Article  PubMed  CAS  Google Scholar 

  29. Segel, M.J., G. Izbicki, P.Y. Cohen, R. Or, T.G. Christensen, S.B. Wallach-Dayan, and R. Breuer. 2003. Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 285 (6): L1255–L1262.

    Article  PubMed  CAS  Google Scholar 

  30. Strieter, R.M., K.M. Starko, R.I. Enelow, I. Noth, and V.G. Valentine. 2004. Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 170 (2): 133–140.

    Article  PubMed  Google Scholar 

  31. Suga, M., K. Iyonaga, H. Ichiyasu, N. Saita, H. Yamasaki, and M. Ando. 1999. Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. The European Respiratory Journal 14 (2): 376–382.

    Article  PubMed  CAS  Google Scholar 

  32. Takizawa, H., M. Satoh, H. Okazaki, G. Matsuzaki, N. Suzuki, A. Ishii, M. Suko, H. Okudaira, Y. Morita, and K. Ito. 1997. Increased IL-6 and IL-8 in bronchoalveolar lavage fluids (BALF) from patients with sarcoidosis: Correlation with the clinical parameters. Clinical and Experimental Immunology 107 (1): 175–181.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Teng, X., Z. Hu, X. Wei, Z. Wang, T. Guan, N. Liu, X. Liu, N. Ye, G. Deng, C. Luo, N. Huang, C. Sun, M. Xu, X. Zhou, H. Deng, C.K. Edwards, X. Chen, X. Wang, K. Cui, Y. Wei, and J. Li. 2014. IL-37 ameliorates the inflammatory process in psoriasis by suppressing proinflammatory cytokine production. Journal of Immunology 192 (4): 1815–1823.

    Article  CAS  Google Scholar 

  34. Tulek, B., E. Kiyan, H. Toy, A. Kiyici, C. Narin, and M. Suerdem. 2011. Anti-inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats. Clinical and Investigative Medicine 34 (6): E341.

    Article  PubMed  CAS  Google Scholar 

  35. Wilson, M.S., S.K. Madala, T.R. Ramalingam, B.R. Gochuico, I.O. Rosas, A.W. Cheever, and T.A. Wynn. 2010. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. The Journal of Experimental Medicine 207 (3): 535–552.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Wu, B., K. Meng, Q. Ji, M. Cheng, K. Yu, X. Zhao, H. Tony, Y. Liu, Y. Zhou, C. Chang, Y. Zhong, Z. Zhu, W. Zhang, X. Mao, and Q. Zeng. 2014. Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice. Clinical and Experimental Immunology 176 (3): 438–451.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Yang, Y., Z.X. Zhang, D. Lian, A. Haig, R.N. Bhattacharjee, and A.M. Jevnikar. 2015. IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia-reperfusion injury. Kidney International 87 (2): 396–408.

    Article  PubMed  CAS  Google Scholar 

  38. Ye, L., L. Ji, Z. Wen, Y. Zhou, D. Hu, Y. Li, T. Yu, B. Chen, J. Zhang, L. Ding, J. du, and Z. Huang. 2014. IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: Its correlation with disease activity. Journal of Translational Medicine 12: 69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Zhang, K., M. Gharaee-Kermani, M.L. Jones, J.S. Warren, and S.H. Phan. 1994. Lung monocyte chemoattractant protein-1 gene expression in bleomycin-induced pulmonary fibrosis. Journal of Immunology 153 (10): 4733–4741.

    CAS  Google Scholar 

  40. Ziesche, R., E. Hofbauer, K. Wittmann, V. Petkov, and L.H. Block. 1999. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. The New England Journal of Medicine 341 (17): 1264–1269.

    Article  PubMed  CAS  Google Scholar 

  41. Zuo, F., N. Kaminski, E. Eugui, J. Allard, Z. Yakhini, A. Ben-Dor, L. Lollini, D. Morris, Y. Kim, B. DeLustro, D. Sheppard, A. Pardo, M. Selman, and R.A. Heller. 2002. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proceedings of the National Academy of Sciences of the United States of America 99 (9): 6292–6297.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

This study was supported by Zhejiang Provincial Natural Science Foundation of China (LY18H010003, LY17H010001), Natural Science Foundation of Ningbo (2017A610249, 2017A610248, 2016A610088), and Public Welfare Technology Application Project of Zhejiang Province of China (2016C37139) and sponsored by K.C. Wong Magna Fund in Ningbo University.

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  1. Yan Li and Qiaoyan Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, 315211, China

    Yan Li, Qiaoyan Gao, Keye Xu, Xiao Peng, Xianli Yuan, Wenwen Jiang & Mingcai Li

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  1. Yan Li
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  2. Qiaoyan Gao
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Correspondence to Wenwen Jiang or Mingcai Li.

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All experiments were approved by the Animal Ethics Committee of Ningbo University.

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Li, Y., Gao, Q., Xu, K. et al. Interleukin-37 Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice. Inflammation 41, 1772–1779 (2018). https://doi.org/10.1007/s10753-018-0820-9

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