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IL-6 induced proliferation and cytotoxic activity of CD8+ T cells is elevated by SUMO2 overexpression

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Abstract

T cells play an important role in adaptive immune responses that destroy pathogens or infected cells. Therefore, regulation of T cell activity is important in various diseases, such as autoimmune diseases, hypersensitivity, and cancer. The conjugation of small ubiquitin-related modifier (SUMO) is a post-translational protein modification that regulates activity, stability, and subcellular translocation of target proteins. In this study, CD8+ T cells overexpressing SUMO2 showed greater proliferation and cytotoxic activity against tumor cells in the presence of IL-6 than wild-type CD8+ T cells in vitro. These CD8+ T cell functions were suppressed during treatment with MEK1 or PI3K-specific inhibitors. Therefore, our findings suggest that IL-6-derived signaling pathways, including the MEK1 and PI3K pathways, are upregulated by SUMO2 overexpression. However, transgenic expression of SUMO2 in T cells did not modulate Th1/2 balance. Collectively, our results showed that SUMO2-Tg promotes cytotoxic activity against tumor cells by increasing the proliferation and cytotoxicity of CD8+ T cells.

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References

  • Berg NN, Puente LG, Dawicki W, Ostergaard HL (1998) Sustained TCR signaling is required for mitogen-activated protein kinase activation and degranulation by cytotoxic T lymphocytes. J Immunol 161:2919–2924

    CAS  PubMed  Google Scholar 

  • Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D (2004) A M55 V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 279:27233–27238

    Article  CAS  PubMed  Google Scholar 

  • Dai Y, Rahmani M, Pei XY, Khanna P, Han SI, Mitchell C, Dent P, Grant S (2005) Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 105:1706–1716

    Article  CAS  PubMed  Google Scholar 

  • Desterro JM, Rodriguez MS, Hay RT (1998) SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 2:233–239

    Article  CAS  PubMed  Google Scholar 

  • Garman RD, Jacobs KA, Clark SC, Raulet DH (1987) B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci USA 84:7629–7633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY (2004) A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 36:837–841

    Article  CAS  PubMed  Google Scholar 

  • Hahn M, Li W, Yu C, Rahmani M, Dent P, Grant S (2005) Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 4:457–470

    CAS  PubMed  Google Scholar 

  • Hay RT (2005) SUMO: a history of modification. Mol Cell 18:1–12

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu CC, Chen JK (2010) Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. J Cell Physiol 223:343–351

    CAS  PubMed  Google Scholar 

  • Manza LL, Codreanu SG, Stamer SL, Smith DL, Wells KS, Roberts RL, Liebler DC (2004) Global shifts in protein sumoylation in response to electrophile and oxidative stress. Chem Res Toxicol 17:1706–1715

    Article  CAS  PubMed  Google Scholar 

  • Mccubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708–722

    Article  CAS  PubMed  Google Scholar 

  • Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T (1988) IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol 141:1543–1549

    CAS  PubMed  Google Scholar 

  • Ouyang J, Valin A, Gill G (2009) Regulation of transcription factor activity by SUMO modification. Methods Mol Biol 497:141–152

    Article  CAS  PubMed  Google Scholar 

  • Puente LG, He JS, Ostergaard HL (2006) A novel PKC regulates ERK activation and degranulation of cytotoxic T lymphocytes: plasticity in PKC regulation of ERK. Eur J Immunol 36:1009–1018

    Article  CAS  PubMed  Google Scholar 

  • Sia C (2005) Is a new immune response mediator in the NF-kappaB pathway–SUMO-4–related to type 1 diabetes? Rev Diabet Stud 2:58–60

    Article  PubMed  PubMed Central  Google Scholar 

  • Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S (1998) Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 161:4652–4660

    CAS  PubMed  Google Scholar 

  • Treuter E, Gustafsson JA (2007) Wrestling rules in transrepression: as easy as SUMO-1, -2, -3? Mol Cell 25:178–180

    Article  CAS  PubMed  Google Scholar 

  • Wang CY, Yang P, Li M, Gong F (2009) Characterization of a negative feedback network between SUMO4 expression and NFkappaB transcriptional activity. Biochem Biophys Res Commun 381:477–481

    Article  CAS  PubMed  Google Scholar 

  • Won TJ, Lee YJ, Hyung KE, Yang E, Sohn UD, Min HY, Lee Do I, Park SY, Hwang KW (2015) SUMO2 overexpression enhances the generation and function of interleukin-17-producing CD8(+) T cells in mice. Cell Signal 27:1246–1252

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Paschen W (2009) Gene expression and cell growth are modified by silencing SUMO2 and SUMO3 expression. Biochem Biophys Res Commun 382:215–218

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Sheng H, Homi HM, Warner DS, Paschen W (2008) Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation–a new target for therapeutic intervention? J Neurochem 106:989–999

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by the Chung-Ang University Excellent Student Scholarship and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2009620).

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Correspondence to Kwang Woo Hwang.

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The authors hereby declare that they have no conflict of interest.

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Yun-Jung Lee, Tae Joon Won and Kyeong Eun Hyung contributed equally to this work

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Lee, YJ., Won, T.J., Hyung, K.E. et al. IL-6 induced proliferation and cytotoxic activity of CD8+ T cells is elevated by SUMO2 overexpression. Arch. Pharm. Res. 39, 705–712 (2016). https://doi.org/10.1007/s12272-016-0736-6

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  • DOI: https://doi.org/10.1007/s12272-016-0736-6

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