Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Intracellular mature IL-37 suppresses tumor metastasis via inhibiting Rac1 activation

Oncogene volume 37, pages 1095–1106 (2018)Cite this article

Subjects

Abstract

IL-37, a newly found anti-inflammatory cytokine of the IL-1 family, has both extracellular and intracellular functions. Accumulating evidences indicate that it is also involved in tumor progression. However, the mechanism and its intracellular target are unclear. In this study, clinical data from 84 patients showed that loss or reduced expression of IL-37 in lung adenocarcinoma tissues was significantly associated with tumor metastasis. We further provided evidence that IL-37 inhibited effectively tumor metastasis in vitro and in vivo. Moreover, we uncovered a novel mechanism by which IL-37 suppressed tumor cell migration via its intracellular mature form (amino acids 46–218). Intracellular mature form of IL-37, but not its extracellular form, markedly inhibited migration of multiple kinds of tumor cells through inhibiting Rac1 activation. Mechanistically, intracellular mature IL-37 directly bound to the CAAX motif in the C-terminal hypervariable region of Rac1, and then inhibited Rac1 membrane translocation and subsequent downstream signaling. Our research identifies intracellular mature IL-37 as a novel endogenous inhibitor of Rac1. Given the crucial roles of Rac1 in tumor angiogenesis and metastasis, intracellular mature IL-37 might serve as a potential strategy for the control of Rac1 activity and tumor progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE et al. Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem 2000; 275: 10308–10314.

    Article  CAS  PubMed  Google Scholar 

  2. Busfield SJ, Comrack CA, Yu G, Chickering TW, Smutko JS, Zhou H et al. Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 2000; 66: 213–216.

    Article  CAS  PubMed  Google Scholar 

  3. Boraschi D, Lucchesi D, Hainzl S, Leitner M, Maier E, Mangelberger D et al. IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur Cytokine Network 2011; 22: 127–147.

    CAS  Google Scholar 

  4. Quirk S, Agrawal DK . Immunobiology of IL-37: mechanism of action and clinical perspectives. Exp Rev Clin Immunol 2014; 10: 1703–1709.

    Article  CAS  Google Scholar 

  5. Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA . IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 2010; 11: 1014–1022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gao W, Kumar S, Lotze MT, Hanning C, Robbins PD, Gambotto A . Innate immunity mediated by the cytokine IL-1 homologue 4 (IL-1H4/IL-1F7) induces IL-12-dependent adaptive and profound antitumor immunity. J Immunol 2003; 170: 107–113.

    Article  CAS  PubMed  Google Scholar 

  7. Luo Y, Cai X, Liu S, Wang S, Nold-Petry CA, Nold MF et al. Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells. Proc Natl Acad Sci USA 2014; 111: 15178–15183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McNamee EN, Masterson JC, Jedlicka P, McManus M, Grenz A, Collins CB et al. Interleukin 37 expression protects mice from colitis. Proc Natl Acad Sci USA 2011; 108: 16711–16716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Coll-Miro M, Francos-Quijorna I, Santos-Nogueira E, Torres-Espin A, Bufler P, Dinarello CA et al. Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci USA 2016; 113: 1411–1416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ballak DB, van Diepen JA, Moschen AR, Jansen HJ, Hijmans A, Groenhof GJ et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun 2014; 5: 4711.

    Article  CAS  PubMed  Google Scholar 

  11. Li S, Neff CP, Barber K, Hong J, Luo Y, Azam T et al. Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8. Proc Natl Acad Sci USA 2015; 112: 2497–2502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ye L, Jiang B, Deng J, Du J, Xiong W, Guan Y et al. IL-37 alleviates rheumatoid arthritis by suppressing IL-17 and IL-17-triggering cytokine production and limiting Th17 cell proliferation. J Immunol 2015; 194: 5110–5119.

    Article  CAS  PubMed  Google Scholar 

  13. Moretti S, Bozza S, Oikonomou V, Renga G, Casagrande A, Iannitti RG et al. IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis. PLoS Pathog 2014; 10: e1004462.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ye L, Ji L, Wen Z, Zhou Y, Hu D, Li Y et al. IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: its correlation with disease activity. J Transl Med 2014; 12: 69.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lunding L, Webering S, Vock C, Schroder A, Raedler D, Schaub B et al. IL-37 requires IL-18Ralpha and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice. Allergy 2015; 70: 366–373.

    Article  CAS  PubMed  Google Scholar 

  16. Bulau AM, Fink M, Maucksch C, Kappler R, Mayr D, Wagner K et al. In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. Sci World J 2011; 11: 2480–2490.

    Article  Google Scholar 

  17. Wu B, Meng K, Ji Q, Cheng M, Yu K, Zhao X et al. Interleukin-37 ameliorates myocardial ischemia/reperfusion injury in mice. Clin Exp immunol 2014; 176: 438–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Teng X, Hu Z, Wei X, Wang Z, Guan T, Liu N et al. IL-37 ameliorates the inflammatory process in psoriasis by suppressing proinflammatory cytokine production. J Immunol 2014; 192: 1815–1823.

    Article  CAS  PubMed  Google Scholar 

  19. Chai M, Ji Q, Zhang H, Zhou Y, Yang Q, Zhou Y et al. The protective effect of interleukin-37 on vascular calcification and atherosclerosis in apolipoprotein E-deficient mice with diabetes. J Interferon Cytokine Res 2015; 35: 530–539.

    Article  CAS  PubMed  Google Scholar 

  20. Zhao JJ, Pan QZ, Pan K, Weng DS, Wang QJ, Li JJ et al. Interleukin-37 mediates the antitumor activity in hepatocellular carcinoma: role for CD57+ NK cells. Sci Rep 2014; 4: 5177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ge G, Wang A, Yang J, Chen Y, Yang J, Li Y et al. Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer. J Exp Clin Cancer Res 2016; 35: 13.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu R, Tang C, Shen A, Luo H, Wei X, Zheng D et al. IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling. Oncotarget 2016; 7: 85079–85096.

    PubMed  PubMed Central  Google Scholar 

  23. Wang S, An W, Yao Y, Chen R, Zheng X, Yang W et al. Interleukin 37 expression inhibits STAT3 to suppress the proliferation and invasion of human cervical cancer cells. J Cancer 2015; 6: 962–969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 2002; 18: 61–71.

    Article  CAS  PubMed  Google Scholar 

  25. Bulau AM, Nold MF, Li S, Nold-Petry CA, Fink M, Mansell A et al. Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. Proc Natl Acad Sci USA 2014; 111: 2650–2655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dinarello CA, Nold-Petry C, Nold M, Fujita M, Li S, Kim S et al. Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol 2016; 46: 1067–1081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Abulkhir A, Samarani S, Amre D, Duval M, Haddad E, Sinnett D et al. A protective role of IL-37 in cancer: a new hope for cancer patients. J Leukocyte Biol 2016; 101: 395–406.

    Article  PubMed  Google Scholar 

  28. Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP et al. IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 2015; 16: 354–365.

    Article  CAS  PubMed  Google Scholar 

  29. Bosco EE, Mulloy JC, Zheng Y . Rac1 GTPase: a ‘Rac’ of all trades. Cell Mol Life Sci 2009; 66: 370–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rathinam R, Berrier A, Alahari SK . Role of Rho GTPases and their regulators in cancer progression. Front Biosci 2011; 16: 2561–2571.

    Article  CAS  Google Scholar 

  31. Liu S, Yu M, He Y, Xiao L, Wang F, Song C et al. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatol 2008; 47: 1964–1973.

    Article  CAS  Google Scholar 

  32. Li Z, Guo C, Liu X, Zhou C, Zhu F, Wang X et al. TIPE2 suppresses angiogenesis and non-small cell lung cancer (NSCLC) invasiveness via inhibiting Rac1 activation and VEGF expression. Oncotarget 2016; 7: 62224–62239.

    PubMed  PubMed Central  Google Scholar 

  33. Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ et al. Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. Int J Mol Med 2011; 28: 769–776.

    PubMed  Google Scholar 

  34. Lin Y, Zheng Y . Approaches of targeting Rho GTPases in cancer drug discovery. Expert Opin Drug Discov 2015; 10: 991–1010.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zou T, Mao X, Yin J, Li X, Chen J, Zhu T et al. Emerging roles of RAC1 in treating lung cancer patients. Clin Genet 2016; 91: 520–528.

    Article  PubMed  Google Scholar 

  36. Kreis P, Barnier JV . PAK signalling in neuronal physiology. Cell Gignal 2009; 21: 384–393.

    Article  CAS  Google Scholar 

  37. Wang CQ, Sun HT, Gao XM, Ren N, Sheng YY, Wang Z et al. Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression. Am J Cancer Res 2016; 6: 1873–1889.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q et al. TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA 2012; 109: 15413–15418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Smithers CC, Overduin M . Structural mechanisms and drug discovery prospects of rho GTPases. Cells 2016; 5: 2.

    Article  Google Scholar 

  40. Yan X, Zhao J, Zhang R . Interleukin-37 mediates the antitumor activity in colon cancer through beta-catenin suppression. Oncotarget 2017; 8: 49064–49075.

    PubMed  PubMed Central  Google Scholar 

  41. Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C et al. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer 2013; 12: 149.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cherfils J, Zeghouf M . Chronicles of the GTPase switch. Nat Chem Biol 2011; 7: 493–495.

    Article  CAS  PubMed  Google Scholar 

  43. Karnoub AE, Symons M, Campbell SL, Der CJ . Molecular basis for Rho GTPase signaling specificity. Breast Cancer Res Treat 2004; 84: 61–71.

    Article  CAS  PubMed  Google Scholar 

  44. Cherfils J, Zeghouf M . Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 2013; 93: 269–309.

    Article  CAS  PubMed  Google Scholar 

  45. Wittinghofer A, Vetter IR . Structure-function relationships of the G domain, a canonical switch motif. Annu Rev Biochem 2011; 80: 943–971.

    Article  CAS  PubMed  Google Scholar 

  46. Michaelson D, Silletti J, Murphy G, D'Eustachio P, Rush M, Philips MR . Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J Cell Biol 2001; 152: 111–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lanning CC, Daddona JL, Ruiz-Velasco R, Shafer SH, Williams CL . The Rac1 C-terminal polybasic region regulates the nuclear localization and protein degradation of Rac1. J Biol Chem 2004; 279: 44197–44210.

    Article  CAS  PubMed  Google Scholar 

  48. Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR . The Rac1 polybasic region is required for interaction with its effector PRK1. J Biol Chem 2008; 283: 1492–1500.

    Article  CAS  PubMed  Google Scholar 

  49. Schaefer A, Reinhard NR, Hordijk PL . Toward understanding RhoGTPase specificity: structure, function and local activation. Small GTPases 2014; 5: 6.

    Article  PubMed  Google Scholar 

  50. Gao J, Liao J, Yang GY . CAAX-box protein, prenylation process and carcinogenesis. Am J Transl Res 2009; 1: 312–325.

    PubMed  PubMed Central  Google Scholar 

  51. Chen YH, Zhou BY, Wu XJ, Xu JF, Zhang JA, Chen YH et al. CCL22 and IL-37 inhibit the proliferation and epithelial-mesenchymal transition process of NSCLC A549 cells. Oncol Rep 2016; 36: 2017–2024.

    Article  CAS  PubMed  Google Scholar 

  52. Fang D, Chen H, Zhu JY, Wang W, Teng Y, Ding HF et al. Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. Oncogene 2017; 36: 1546–1558.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research is supported by the national key research and development plan of China (No. 2016YFC1303405), the National Natural Science Foundation of China (31470856 and 91439124), Shandong Provincial Natural Science Foundation, China (2014GSF118076, ZR2011HZ003), the Fundamental Research Funds of Shandong University (2014QY004) and Major Project of Science and Technology of Shandong Province (2015ZDJS04001). WC is supported by the Intramural Research Program of NIH, NIDCR, USA.

Author information

Authors and Affiliations

  1. Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, Jinan, China

    Y Li, M Zhao, C Guo, H Chu, W Li, X Chen, X Wang, Y Li, Y Jia, S Koussatidjoa, F Zhu, J Wang, X Wang, Q Wang, W Zhao, Y Shi & L Zhang

  2. Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA

    W Chen

Authors
  1. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Koussatidjoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Q Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. W Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Y Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Zhao, M., Guo, C. et al. Intracellular mature IL-37 suppresses tumor metastasis via inhibiting Rac1 activation. Oncogene 37, 1095–1106 (2018). https://doi.org/10.1038/onc.2017.405

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.405

This article is cited by

Search

Advanced search

Quick links