Molecular and Cellular Biochemistry

, Volume 461, Issue 1–2, pp 119–126 | Cite as

TGF-β2 antagonizes IL-6-promoted cell survival

  • Yuping Du
  • Jingjie Sun
  • Xinning Liu
  • Jing Nan
  • Xiaodong Qin
  • Xiao Wang
  • Jihui Guo
  • Chenyang ZhaoEmail author
  • Jinbo YangEmail author


Transforming growth factor beta is a key cytokine involved in the pathogenesis of fibrosis in many organs, whereas interleukin-6 plays an important role in the regulation of inflammation. They are both potent angiogenesis inducers with opposite effects on cell survival and apoptosis. TGF-β2 induces apoptosis; in contrast, IL-6 protects cells from apoptosis. The possible interaction between these two cytokines is indicated in various disease states. In this study, we have assessed the effect of TGF-β2 on IL-6 signaling and found that TGF-β2 could strongly inhibit IL-6-induced STAT3 activation and synergy with IL-6 resulting in enhanced SOCS3 expression. Interestingly, IL-6 also slows down the decay of TGF-β2 mRNA. Consistent with this mechanism, we found that TGF-β2 could antagonize IL-6 effect on cell survival in both γ-irradiation and UV light-induced apoptosis. Taken together, the finding shows that TGF-β2 serves as a negative regulator of IL-6 signaling and antagonizes the anti-apoptosis effect of IL-6.


IL-6 TGF-β2 STAT3 Cell survival Apoptosis 



This work was supported by Grant 31571439 from National Natural Science Foundation of China (J.Y.), Qingdao Scientific and Technological Innovation center for Marine Biomedicine Development Grant (2017-CXZX01-2-2), and startup funding of Ocean University of China (C.Z.).

Compliance with ethical standards

Conflicts of interest

The authors disclose no potential conflicts of interest.


  1. 1.
    Santibanez JF, Quintanilla M, Bernabeu C (2011) TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci 121:233–251CrossRefGoogle Scholar
  2. 2.
    Penn JW, Grobbelaar AO, Rolfe KJ (2012) The role of the TGF-beta family in wound healing, burns and scarring: a review. Int J Burns Trauma 2:18–28PubMedPubMedCentralGoogle Scholar
  3. 3.
    Derynck R, Miyazono K (2008) The TGF-[beta] family. CSHL Press, New YorkGoogle Scholar
  4. 4.
    Buck MB, Knabbe C (2006) TGF-beta signaling in breast cancer. Ann N Y Acad Sci 1089:119–126CrossRefGoogle Scholar
  5. 5.
    Padua D, Massagué J (2009) Roles of TGFβ in metastasis. Cell Res 19:89–102CrossRefGoogle Scholar
  6. 6.
    Massagué J, Gomis RR (2006) The logic of TGFβ signaling. FEBS Lett 580:2811–2820CrossRefGoogle Scholar
  7. 7.
    Namachivayam K, Blanco CL, MohanKumar K, Jagadeeswaran R, Vasquez M, McGill-Vargas L, Garzon SA, Jain SK, Gill RK, Freitag NE, Weitkamp JH, Seidner SR, Maheshwari A (2013) Smad7 inhibits autocrine expression of TGF-beta2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 304:G167–G180CrossRefGoogle Scholar
  8. 8.
    Levy DE, Darnell J (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662CrossRefGoogle Scholar
  9. 9.
    Raz R, Durbin JE, Levy DE (1994) Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J Biol Chem 269:24391–24395PubMedGoogle Scholar
  10. 10.
    Catlett-Falcone R, Dalton WS, Jove R (1999) STAT proteins as novel targets for cancer therapy. Curr Opin Oncol 11:490CrossRefGoogle Scholar
  11. 11.
    Lin TS, Mahajan S, Frank DA (2000) STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19:2496–2504CrossRefGoogle Scholar
  12. 12.
    Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE (1999) Stat3 as an oncogene. Cell 98:295–303CrossRefGoogle Scholar
  13. 13.
    Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499–2513CrossRefGoogle Scholar
  14. 14.
    Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, Swamy SN, Ahn KS, Kumar AP, Tan BK, Hui KM, Sethi G (2013) Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta 1835:46–60PubMedGoogle Scholar
  15. 15.
    Wang G, Yu Y, Sun C, Liu T, Liang T, Zhan L, Lin X, Feng XH (2016) STAT3 selectively interacts with Smad3 to antagonize TGF-beta signalling. Oncogene 35:4388–4398CrossRefGoogle Scholar
  16. 16.
    Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, Iida M, Kobayashi T, Yoshimura A (2006) Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene 25:2520–2530CrossRefGoogle Scholar
  17. 17.
    Qin H, Wang L, Feng T, Elson CO, Niyongere SA, Lee SJ, Reynolds SL, Weaver CT, Roarty K, Serra R, Benveniste EN, Cong Y (2009) TGF-beta promotes Th17 cell development through inhibition of SOCS3. J Immunol 183:97–105CrossRefGoogle Scholar
  18. 18.
    Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev 21:1396–1408CrossRefGoogle Scholar
  19. 19.
    Banerjee K, Resat H (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer 138:2570–2578CrossRefGoogle Scholar
  20. 20.
    Litherland GJ, Elias MS, Hui W, Macdonald CD, Catterall JB, Barter MJ, Farren MJ, Jefferson M, Rowan AD (2010) Protein kinase C isoforms zeta and iota mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction. J Biol Chem 285:22414–22425CrossRefGoogle Scholar
  21. 21.
    Samsonov A, Zenser N, Zhang F, Zhang H, Fetter J, Malkov D (2013) Tagging of genomic STAT3 and STAT1 with fluorescent proteins and insertion of a luciferase reporter in the cyclin D1 gene provides a modified A549 cell line to screen for selective STAT3 inhibitors. PLoS ONE 8:e68391. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li Y, de Haar C, Chen M, Deuring J, Gerrits MM, Smits R, Xia B, Kuipers EJ, van der Woude CJ (2010) Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 59:227–235CrossRefGoogle Scholar
  23. 23.
    Ray S, Ju X, Sun H, Finnerty CC, Herndon DN, Brasier AR (2013) The IL-6 trans-signaling-STAT3 pathway mediates ECM and cellular proliferation in fibroblasts from hypertrophic scar. J Invest Dermatol 133:1212–1220CrossRefGoogle Scholar
  24. 24.
    Keene JD (2001) Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome. Proc Natl Acad Sci USA 98:7018–7024CrossRefGoogle Scholar
  25. 25.
    Schindler C, Darnell JE Jr (1995) Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem 64:621–651CrossRefGoogle Scholar
  26. 26.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809CrossRefGoogle Scholar
  27. 27.
    Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH (2002) TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4:51–58CrossRefGoogle Scholar
  28. 28.
    Derynck R, Feng XH (1997) TGF-beta receptor signaling. Biochim Biophys Acta 1333:F105–F150PubMedGoogle Scholar
  29. 29.
    Dalpke AH, Opper S, Zimmermann S, Heeg K (2001) Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J Immunol 166:7082–7089CrossRefGoogle Scholar
  30. 30.
    Croker BA, Krebs DL, Zhang J-G, Wormald S, Willson TA, Stanley EG, Robb L, Greenhalgh CJ, Förster I, Clausen BE (2003) SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4:540–545CrossRefGoogle Scholar
  31. 31.
    Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjørbæk C, Flier JS (2004) Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10:734–738CrossRefGoogle Scholar
  32. 32.
    Babon JJ, Nicola NA (2012) The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors 30:207–219CrossRefGoogle Scholar
  33. 33.
    Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, Matsuda T (2002) The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun 297:811–817CrossRefGoogle Scholar
  34. 34.
    Bhattacharya S, Schindler C (2003) Regulation of Stat3 nuclear export. J Clin Invest 111:553CrossRefGoogle Scholar
  35. 35.
    Muhammad N, Bhattacharya S, Steele R, Ray RB (2016) Anti-miR-203 suppresses ER-positive breast cancer growth and stemness by targeting SOCS3. Oncotarget 7:58595–58605CrossRefGoogle Scholar
  36. 36.
    Chen XB, Zheng XB, Cai ZX, Lin XJ, Xu MQ (2017) MicroRNA-203 promotes liver regeneration after partial hepatectomy in cirrhotic rats. J Surg Res 211:53–63CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yuping Du
    • 1
  • Jingjie Sun
    • 1
  • Xinning Liu
    • 2
  • Jing Nan
    • 1
  • Xiaodong Qin
    • 1
  • Xiao Wang
    • 1
  • Jihui Guo
    • 1
  • Chenyang Zhao
    • 2
    Email author
  • Jinbo Yang
    • 1
    Email author
  1. 1.School of Life ScienceLanzhou UniversityLanzhouPeople’s Republic of China
  2. 2.School of Medicine and PharmacyOcean University of ChinaShandongPeople’s Republic of China

Personalised recommendations