Skip to main content

Advertisement

SpringerLink
Log in

IL-37 mediates the antitumor activity in renal cell carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Interleukin (IL)-37 is a natural suppressor of innate inflammatory and immune responses. IL-37 plays an important role in renal function and antitumor activity. The aim of this study was to investigate the role of IL-37 in renal cell carcinoma (Rcc). Serum IL-37 levels in 120 Rcc patients and 50 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). The Rcc cell lines A498 and Caki-1 were cultured with 0–100 ng/mL of recombinant human IL-37 protein (rhIL-37). Cancer cells were transfected with or without pcDNA3.1-IL-6 to alter IL-6 expression. Cell migration, proliferation, and apoptosis were tested by wound-healing assay, MTT, and flow cytometry, respectively. Levels of IL-6, pSTAT3 Y705, Bcl-2, cyclin D1, and HIF-1α were detected by qRT-PCR, ELISA, or western blot. Additionally, therapeutic effect of rhIL-37 was also confirmed in SCID mice. The expression of IL-37 was decreased in Rcc patients and was negatively correlated with tumor progression. In vitro, IL-37 markedly inhibited the migration and proliferation, and promoted apoptosis in Rcc cells. Furthermore, the expressions of IL-6, pSTAT3 Y705, HIF-1α, Bcl-2, and cyclin D1 were decreased by IL-37. However, these effects were reversed by the transfection of pcDNA3.1-IL-6. In vivo, tumor growth and gene expressions of IL-6 and HIF-1α were suppressed by IL-37. In conclusion, IL-37 might serve as a novel tumor suppressor in Rcc and exert its antitumor activity through inhibiting IL-6/STAT3 signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60:615–21.

    Article  PubMed  Google Scholar 

  3. Costa LJ, Drabkin HA. Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. Oncologist. 2007;12:1404–15.

    Article  CAS  PubMed  Google Scholar 

  4. Raman R, Vaena D. Immunotherapy in metastatic renal cell carcinoma: a comprehensive review. BioMed Res Int. 2015;2015:367354.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Fitzgerald JP, Nayak B, Shanmugasundaram K, Friedrichs W, Sudarshan S, Eid AA, et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8-production. PLoS ONE. 2012;7:e30712.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Horiguchi A, Oya M, Marumo K, Murai M. STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P. Kidney Int. 2002;61:926–38.

    Article  CAS  PubMed  Google Scholar 

  7. 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;11:1014–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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;70:366–73.

    Article  CAS  PubMed  Google Scholar 

  9. Tete S, Tripodi D, Rosati M, Conti F, Maccauro G, Saggini A, et al. IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation. Int J Immunopathol Pharmacol. 2012;25:31–8.

    CAS  PubMed  Google Scholar 

  10. Yang Y, Zhang ZX, Lian D, Haig A, Bhattacharjee RN, Jevnikar AM. IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia–reperfusion injury. Kidney Int. 2015;87:396–408.

    Article  CAS  PubMed  Google Scholar 

  11. 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 Central  PubMed  Google Scholar 

  12. 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;170:107–13.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Du W, Wang S, Zhou Q, Li X, Chu J, Chang Z, et al. ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer. Oncogene. 2013;32:3319–28.

    Article  CAS  PubMed  Google Scholar 

  15. Liu Q, Jin J, Ying J, Cui Y, Sun M, Zhang L, et al. Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target. Oncotarget. 2015;6:22706–23.

    Article  PubMed  Google Scholar 

  16. Cuadros T, Trilla E, Sarro E, Vila MR, Vilardell J, de Torres I, et al. HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome. Cancer Res. 2014;74:1416–28.

    Article  CAS  PubMed  Google Scholar 

  17. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14:109–19.

    Article  CAS  PubMed  Google Scholar 

  18. Hrab M, Olek-Hrab K, Antczak A, Kwias Z, Milecki T. Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC). Rep Pract Oncol Radiother. 2013;18:304–9.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Polimeno M, Napolitano M, Costantini S, Portella L, Esposito A, Capone F, et al. Regulatory T cells, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), CXCL10, CXCL11, epidermal growth factor (EGF) and hepatocyte growth factor (HGF) as surrogate markers of host immunity in patients with renal cell carcinoma. BJU Int. 2013;112:686–96.

    Article  CAS  PubMed  Google Scholar 

  20. 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;192:1815–23.

    Article  CAS  PubMed  Google Scholar 

  21. Bouali E, Kaabachi W, Hamzaoui A, Hamzaoui K. Interleukin-37 expression is decreased in Behcet’s disease and is associated with inflammation. Immunol Lett. 2015;167:87–94.

    Article  CAS  PubMed  Google Scholar 

  22. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334(Pt 2):297–314.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.

    Article  CAS  PubMed  Google Scholar 

  24. Tomita Y, Bilim V, Kawasaki T, Takahashi K, Okan I, Magnusson KP, et al. Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53. Int J Cancer. 1996;66:322–5.

    Article  CAS  PubMed  Google Scholar 

  25. Huang A, Fone PD, Gandour-Edwards R, White RW, Low RK. Immunohistochemical analysis of BCL-2 protein expression in renal cell carcinoma. J Urol. 1999;162:610–3.

    Article  CAS  PubMed  Google Scholar 

  26. Maruyama R, Yamana K, Itoi T, Hara N, Bilim V, Nishiyama T, et al. Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma. Br J Cancer. 2006;95:1244–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Lima MS, Pereira RA, Costa RS, Tucci S, Dantas M, Muglia VF, et al. The prognostic value of cyclin D1 in renal cell carcinoma. Int Urol Nephrol. 2014;46:905–13.

    Article  CAS  PubMed  Google Scholar 

  28. Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1alpha in renal cell carcinoma tumorigenesis. J Mol Med. 2014;92:825–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Medina Villaamil V, Aparicio Gallego G, Santamarina Cainzos I, Valladares-Ayerbes M, Anton Aparicio LM. Searching for Hif1-alpha interacting proteins in renal cell carcinoma. Clin Transl Oncol. 2012;14:698–708.

    Article  CAS  PubMed  Google Scholar 

  30. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10.

    Article  CAS  PubMed  Google Scholar 

  31. Biswas SK, Lewis CE. NF-kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol. 2010;88:877–84.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We sincerely thank to the colleagues who provided helpful advises for our manuscript writing.

Author information

Authors and Affiliations

  1. Department of Urology, The Third Affiliated Hospital of the Medical College of Xi’an Jiaotong University, Xi’an, 710068, Shaanxi Province, China

    Yazhuo Jiang, Liang Liang, Yang Gao, Juan Chen, Yi Sun, Yongyi Cheng & Yonggang Xu

  2. Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi’an Jiaotong University, 76 Yanta XiLu, Xi’an, 710061, Shaanxi Province, China

    Yili Wang

Authors
  1. Yazhuo Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yili Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongyi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yonggang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yili Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Y., Wang, Y., Liang, L. et al. IL-37 mediates the antitumor activity in renal cell carcinoma. Med Oncol 32, 250 (2015). https://doi.org/10.1007/s12032-015-0695-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-015-0695-7

Keywords

Search

Navigation