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Interleukin-38 overexpression prevents bleomycin-induced mouse pulmonary fibrosis

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Abstract

Pulmonary fibrosis is a kind of pulmonary disorder with chronic inflammation and excessive collagen deposition, and its etiology is not clear. Interleukin (IL)-38 is a new member of IL-1 family cytokines, but its role in pulmonary fibrosis has not been elucidated. In this study, a lentivirus expressing IL-38 was injected into the nasal cavity of mice with bleomycin-induced pulmonary fibrosis. We found that IL-38 overexpression reduced the body weight loss and improved the survival of mice induced by bleomycin. Furthermore, IL-38 expression attenuated the pulmonary inflammation and fibrosis damage induced by bleomycin, decreased the production of pro-inflammatory and pro-fibrotic cytokines such as IL-1β, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor-α, but increased the release of anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) in the lungs of bleomycin-challenged mice. Our data suggest that IL-38 may inhibit bleomycin-induced pulmonary inflammation and fibrosis through its anti-inflammatory effect and regulation of IL-1β/IL-1Ra balance, and IL-38 may be a new strategy for the treatment of pulmonary fibrosis.

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References

  • Adamson IY (1976) Pulmonary toxicity of bleomycin. Environ Health Perspect 16:119–126

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ashcroft T, Simpson JM, Timbrell V (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 41:467–470

    CAS  PubMed  PubMed Central  Google Scholar 

  • Atamas SP, White B (2003) Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine Growth Factor Rev 14:537–550

    CAS  PubMed  Google Scholar 

  • Barlo NP, van Moorsel CH, Korthagen NM, Heron M, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC (2011) Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1beta in idiopathic pulmonary fibrosis. Clin Exp Immunol 166:346–351

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bensen JT, Dawson PA, Mychaleckyj JC, Bowden DW (2001) Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2q12-14. J Interf Cytokine Res 21:899–904

    CAS  Google Scholar 

  • Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W (1996) The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 15:1914–1923

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boutet MA, Najm A, Bart G, Brion R, Touchais S, Trichet V, Layrolle P, Gabay C, Palmer G, Blanchard F, Le Goff B (2017) IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro. Ann Rheum Dis 76:1304–1312

    PubMed  Google Scholar 

  • Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A (1994) Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med 149:655–659

    CAS  PubMed  Google Scholar 

  • Chen Y, Li C, Weng D, Song L, Tang W, Dai W, Yu Y, Liu F, Zhao M, Lu C, Chen J (2014) Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice. Toxicol Appl Pharmacol 275:62–72

    CAS  PubMed  Google Scholar 

  • Chu M, Tam LS, Zhu J, Jiao D, Liu H, Cai Z, Dong J, Kai Lam CW, Wong CK (2017) In vivo anti-inflammatory activities of novel cytokine IL-38 in Murphy Roths Large (MRL)/lpr mice. Immunobiology 222:483–493

    CAS  PubMed  Google Scholar 

  • Claussen CA, Long EC (1999) Nucleic acid recognition by metal complexes of bleomycin. Chem Rev 99:2797–2816

    CAS  PubMed  Google Scholar 

  • Dinarello CA, van der Meer JW (2013) Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 25:469–484

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Q, Li Y, Pan X, Yuan X, Peng X, Li M (2016) Lentivirus expressing soluble ST2 alleviates bleomycin-induced pulmonary fibrosis in mice. Int Immunopharmacol 30:188–193

    CAS  PubMed  Google Scholar 

  • Garraud T, Harel M, Boutet MA, Le Goff B, Blanchard F (2018) The enigmatic role of IL-38 in inflammatory diseases. Cytokine Growth Factor Rev 39:26–35

    CAS  PubMed  Google Scholar 

  • Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I (2007) IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 117:3786–3799

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ge Y, Huang M, Wu Y, Dong N, Yao YM (2020) Interleukin-38 protects against sepsis by augmenting immunosuppressive activity of CD4(+) CD25(+) regulatory T cells. J Cell Mol Med 24:2027–2039

    CAS  PubMed  Google Scholar 

  • Gross TJ, Hunninghake GW (2001) Idiopathic pulmonary fibrosis. N Engl J Med 345:517–525

    CAS  PubMed  Google Scholar 

  • Han Y, Mora J, Huard A, da Silva P, Wiechmann S, Putyrski M, Schuster C, Elwakeel E, Lang G, Scholz A, Scholz T, Schmid T, de Bruin N, Billuart P, Sala C, Burkhardt H, Parnham MJ, Ernst A, Brune B, Weigert A (2019) IL-38 ameliorates skin inflammation and limits IL-17 production from gammadelta T cells. Cell Rep 27(835–846):e835

    Google Scholar 

  • Huang C, Li Y, Fan X, Ma Y, Zhang M, Wang W (2014) IL-17A promotes pulmonary inflammation in rats with pulmonary fibrosis induced by bleomycin. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 30:366–370

    PubMed  Google Scholar 

  • Hubner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B (2008) Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 44(507–511):514–507

    Google Scholar 

  • Izumo T, Kondo M, Nagai A (2009) Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis. Eur Respir J 34:1444–1451

    CAS  PubMed  Google Scholar 

  • Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J (2001) Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 107:1529–1536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Gao Q, Xu K, Peng X, Yuan X, Jiang W, Li M (2018) Interleukin-37 attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice. Inflammation 41:1772–1779

    CAS  PubMed  Google Scholar 

  • Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM, Hansen D, Schweighofer K, Mize NK, Ford JE (2001) Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J Biol Chem 276:20597–20602

    CAS  PubMed  Google Scholar 

  • Luo Y, Laning J, Hayashi M, Hancock PR, Rollins B, Dorf ME (1994) Serologic analysis of the mouse beta chemokine JE/monocyte chemoattractant protein-1. J Immunol 153:3708–3716

    CAS  PubMed  Google Scholar 

  • Maron-Gutierrez T, Castiglione RC, Xisto DG, Oliveira MG, Cruz FF, Pecanha R, Carreira-Junior H, Ornellas DS, Moraes MO, Takiya CM, Rocco PR, Morales MM (2011) Bone marrow-derived mononuclear cell therapy attenuates silica-induced lung fibrosis. Eur Respir J 37:1217–1225

    CAS  PubMed  Google Scholar 

  • Matsuoka M, Kawayama T, Tominaga M, Kaieda S, Tokunaga Y, Kaku Y, Imaoka H, Kinoshita T, Okamoto M, Akiba J, Hoshino T (2019) Attenuated airway eosinophilic inflammations in IL-38 knockout mouse model. Kurume Med J 65:37–46

    PubMed  Google Scholar 

  • Mercurio L, Morelli M, Scarponi C, Eisenmesser EZ, Doti N, Pagnanelli G, Gubinelli E, Mazzanti C, Cavani A, Ruvo M, Dinarello CA, Albanesi C, Madonna S (2018) IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment. Cell Death Dis 9:1104

    PubMed  PubMed Central  Google Scholar 

  • Mi S, Li Z, Yang HZ, Liu H, Wang JP, Ma YG, Wang XX, Liu HZ, Sun W, Hu ZW (2011) Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol 187:3003–3014

    CAS  PubMed  Google Scholar 

  • Moore BB, Hogaboam CM (2008) Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294:L152–L160

    CAS  PubMed  Google Scholar 

  • Moore BB, Paine R 3rd, Christensen PJ, Moore TA, Sitterding S, Ngan R, Wilke CA, Kuziel WA, Toews GB (2001) Protection from pulmonary fibrosis in the absence of CCR2 signaling. J Immunol 167:4368–4377

    CAS  PubMed  Google Scholar 

  • Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, Iwamoto I (1999) Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest 104:5–11

    CAS  PubMed  PubMed Central  Google Scholar 

  • O'Donoghue RJ, Knight DA, Richards CD, Prele CM, Lau HL, Jarnicki AG, Jones J, Bozinovski S, Vlahos R, Thiem S, McKenzie BS, Wang B, Stumbles P, Laurent GJ, McAnulty RJ, Rose-John S, Zhu HJ, Anderson GP, Ernst MR, Mutsaers SE (2012) Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Mol Med 4:939–951

    CAS  PubMed  PubMed Central  Google Scholar 

  • O'Reilly S, Ciechomska M, Cant R, Hugle T, van Laar JM (2012) Interleukin-6, its role in fibrosing conditions. Cytokine Growth Factor Rev 23:99–107

    CAS  PubMed  Google Scholar 

  • Ortiz LA, Lasky J, Lungarella G, Cavarra E, Martorana P, Banks WA, Peschon JJ, Schmidts HL, Brody AR, Friedman M (1999) Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am J Respir Cell Mol Biol 20:825–833

    CAS  PubMed  Google Scholar 

  • Pan X, Xu K, Li Y, Wang X, Peng X, Li M, Li Y (2019) Interleukin-35 expression protects against cigarette smoke-induced lung inflammation in mice. Biomed Pharmacother 110:727–732

    CAS  PubMed  Google Scholar 

  • Phan SH, Kunkel SL (1992) Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 18:29–43

    CAS  PubMed  Google Scholar 

  • Piguet PF, Vesin C (1994) Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J 7:515–518

    CAS  PubMed  Google Scholar 

  • Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P (1989) Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 170:655–663

    CAS  PubMed  Google Scholar 

  • Rudloff I, Godsell J, Nold-Petry CA, Harris J, Hoi A, Morand EF, Nold MF (2015) Brief report: Interleukin-38 exerts antiinflammatory functions and is associated with disease activity in systemic lupus erythematosus. Arthritis Rheumatol 67:3219–3225

    CAS  PubMed  Google Scholar 

  • Saito F, Tasaka S, Inoue K, Miyamoto K, Nakano Y, Ogawa Y, Yamada W, Shiraishi Y, Hasegawa N, Fujishima S, Takano H, Ishizaka A (2008) Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol 38:566–571

    CAS  PubMed  Google Scholar 

  • Sheppard D (2006) Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc 3:413–417

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sleijfer S (2001) Bleomycin-induced pneumonitis. Chest 120:617–624

    CAS  PubMed  Google Scholar 

  • Suga M, Iyonaga K, Ichiyasu H, Saita N, Yamasaki H, Ando M (1999) Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. Eur Respir J 14:376–382

    CAS  PubMed  Google Scholar 

  • Sun X, Hou T, Cheung E, Iu TN, Tam VW, Chu IM, Tsang MS, Chan PK, Lam CW, Wong CK (2019) Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma. Cell Mol Immunol

  • Tan HL, Rosenthal M (2013) IL-17 in lung disease: friend or foe? Thorax 68:788–790

    PubMed  Google Scholar 

  • Todd NW, Luzina IG, Atamas SP (2012) Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair 5:11

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tominaga M, Okamoto M, Kawayama T, Matsuoka M, Kaieda S, Sakazaki Y, Kinoshita T, Mori D, Inoue A, Hoshino T (2017) Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis. Respir Investig 55:293–299

    PubMed  Google Scholar 

  • van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, Joosten LA, van der Meer JW, Hao R, Kalabokis V, Dinarello CA (2012) IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc Natl Acad Sci U S A 109:3001–3005

    PubMed  PubMed Central  Google Scholar 

  • Wang Q, Wang Y, Hyde DM, Gotwals PJ, Koteliansky VE, Ryan ST, Giri SN (1999) Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax 54:805–812

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson MS, Wynn TA (2009) Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol 2:103–121

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA (2010) Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med 207:535–552

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie C, Yan W, Quan R, Chen C, Tu L, Hou X, Fu Y (2020) Interleukin-38 is elevated in inflammatory bowel diseases and suppresses intestinal inflammation. Cytokine 127:154963

    CAS  PubMed  Google Scholar 

  • Xu F, Lin S, Yan X, Wang C, Tu H, Yin Y, Cao J (2018) Interleukin 38 protects against lethal sepsis. J Infect Dis 218:1175–1184

    PubMed  Google Scholar 

  • Xu K, Sun J, Chen S, Li Y, Peng X, Li M, Li Y (2019) Hydrodynamic delivery of IL-38 gene alleviates obesity-induced inflammation and insulin resistance. Biochem Biophys Res Commun 508:198–202

    CAS  PubMed  Google Scholar 

  • Yuan X, Li Y, Pan X, Peng X, Song G, Jiang W, Gao Q, Li M (2016) IL-38 alleviates concanavalin A-induced liver injury in mice. Int Immunopharmacol 40:452–457

    CAS  PubMed  Google Scholar 

  • Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN (1993) Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 150:4188–4196

    CAS  PubMed  Google Scholar 

  • Zhu Y, Liu Y, Zhou W, Xiang R, Jiang L, Huang K, Xiao Y, Guo Z, Gao J (2010) A prostacyclin analogue, iloprost, protects from bleomycin-induced pulmonary fibrosis in mice. Respir Res 11:34

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81970735), Natural Science Foundation of Zhejiang Province (LY17H010001, LY18H010003), and sponsored by K.C. Wong Magna Fund in Ningbo University.

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Authors and Affiliations

  1. Ningbo University School of Medicine, Ningbo, 315211, Zhejiang, China

    Zhiwei Xu, Xianli Yuan, Qiaoyan Gao, Yan Li & Mingcai Li

  2. Department of Critical Care Medicine, Ningbo Medical Center, Li Huili Hospital, Jiangnan Road 1111, Ningbo, 315103, Zhejiang, China

    Zhiwei Xu

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  1. Zhiwei Xu
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Contributions

Zhiwei Xu and Xianli Yuan contributed equally to this work. Z.X. and X.Y. performed the molecular biological and animal studies, and wrote the manuscript; Q.G. performed the biochemical analysis and ELISA; Y.L. and M.L. conceived the study, performed the data analysis, and revised the manuscript; and all authors reviewed and approved the final manuscript. All data were generated in-house and that no paper mill was used.

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Correspondence to Mingcai Li.

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All animal procedures were in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition, NIH) and approved by The Laboratory Animal Ethics Committee of Ningbo University School of Medicine.

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Xu, Z., Yuan, X., Gao, Q. et al. Interleukin-38 overexpression prevents bleomycin-induced mouse pulmonary fibrosis. Naunyn-Schmiedeberg's Arch Pharmacol 394, 391–399 (2021). https://doi.org/10.1007/s00210-020-01920-3

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