Advertisement

Molecules and Cells

, 32:265 | Cite as

IL-15-induced IL-10 increases the cytolytic activity of human natural killer cells

  • Ju Yeong Park
  • Suk Hyung Lee
  • Suk-Ran Yoon
  • Young-Jun Park
  • Haiyoung Jung
  • Tae-Don KimEmail author
  • Inpyo ChoiEmail author
Article

Abstract

Interleukin 10 (IL-10) is a multifunctional cytokine that regulates diverse functions of immune cells. Natural killer (NK) cells express the IL-10 and IL-10 receptor, but little is known about the function of IL-10 on NK cell activation. In this study, we show the expression and role of IL-10 in human NK cells. Among the cytokines tested, IL-15 was the most potent inducer of IL-10, with a maximal peak expression at 5 h after treatment. Furthermore, IL-10 receptor was shown to be expressed in NK cells. IL-10 alone had a significant effect on NK cytotoxicity which additively increased NK cell cytotoxicity in the presence of IL-15. Neutralizing IL-10 with anti-IL-10 antibody suppressed the inductive effect of IL-10 on NK cell cytotoxicity; however, IL-10 had no effect on IFN-γ or TNF-α production or NK cell activatory receptor expression. STAT signals are implicated as a key mediator of IL-10/IL-15 cytotoxicity response. Thus, the effect of IL-10 on NK cells is particularly interesting with regard to the STAT3 signal that was enhanced by IL-10 or IL-15.

Keywords

cytotoxicity IL-10 IL-15 natural killer cell 

References

  1. Alter, G., Kavanagh, D., Rihn, S., Luteijn, R., Brooks, D., Oldstone, M., van Lunzen, J., and Altfeld, M. (2010). IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection. J. Clin. Invest. 120, 1905–1913.PubMedCrossRefGoogle Scholar
  2. Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L., and Powrie, F. (1999). An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004.PubMedCrossRefGoogle Scholar
  3. Becknell, B., and Caligiuri, M.A. (2005). Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv. Immunol. 86, 209–239.PubMedCrossRefGoogle Scholar
  4. D’Andrea, A., Aste-Amezaga, M., Valiante, N.M., Ma, X., Kubin, M., and Trinchieri, G. (1993). Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178, 1041–1048.PubMedCrossRefGoogle Scholar
  5. de Waal Malefyt, R., Haanen, J., Spits, H., Roncarolo, M.G., te Velde, A., Figdor, C., Johnson, K., Kastelein, R., Yssel, H., and de Vries, J.E. (1991). Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J. Exp. Med. 174, 915–924.PubMedCrossRefGoogle Scholar
  6. Dubois, S., Patel, H.J., Zhang, M., Waldmann, T.A., and Muller, J.R. (2008). Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J. Immunol. 180, 2099–2106.PubMedGoogle Scholar
  7. Fiorentino, D.F., Bond, M.W., and Mosmann, T.R. (1989). Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 170, 2081–2095.PubMedCrossRefGoogle Scholar
  8. Hunter, C.A., Ellis-Neyer, L., Gabriel, K.E., Kennedy, M.K., Grabstein, K.H., Linsley, P.S., and Remington, J.S. (1997a). The role of the CD28/B7 interaction in the regulation of NK cell responses during infection with Toxoplasma gondii. J. Immunol. 158, 2285–2293.PubMedGoogle Scholar
  9. Hunter, C.A., Gabriel, K.E., Radzanowski, T., Neyer, L.E., and Remington, J.S. (1997b). Type I interferons enhance production of IFN-gamma by NK cells. Immunol. Lett. 59, 1–5.PubMedCrossRefGoogle Scholar
  10. Hunter, C.A., Timans, J., Pisacane, P., Menon, S., Cai, G., Walker, W., Aste-Amezaga, M., Chizzonite, R., Bazan, J.F., and Kastelein, R.A. (1997c). Comparison of the effects of interleukin-1 alpha, interleukin-1 beta and interferon-gamma-inducing factor on the production of interferon-gamma by natural killer. Eur. J. Immunol. 27, 2787–2792.PubMedCrossRefGoogle Scholar
  11. Kennedy, M.K., Glaccum, M., Brown, S.N., Butz, E.A., Viney, J.L., Embers, M., Matsuki, N., Charrier, K., Sedger, L., Willis, C.R., et al. (2000). Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780.PubMedCrossRefGoogle Scholar
  12. Lanier, L.L., and Phillips, J.H. (1992). Natural killer cells. Curr. Opin. Immunol. 4, 38–42.PubMedCrossRefGoogle Scholar
  13. Ma, A., Boone, D.L., and Lodolce, J.P. (2000). The pleiotropic functions of interleukin 15: not so interleukin 2-like after all. J. Exp. Med. 191, 753–756.PubMedCrossRefGoogle Scholar
  14. Ma, A., Koka, R., and Burkett, P. (2006). Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu. Rev. Immunol. 24, 657–679.PubMedCrossRefGoogle Scholar
  15. Mocellin, S., Panelli, M., Wang, E., Rossi, C.R., Pilati, P., Nitti, D., Lise, M., and Marincola, F.M. (2004). IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun. 5, 621–630.PubMedCrossRefGoogle Scholar
  16. Moore, K.W., O’Garra, A., de Waal Malefyt, R., Vieira, P., and Mosmann, T.R. (1993). Interleukin-10. Annu. Rev. Immunol. 11, 165–190.PubMedCrossRefGoogle Scholar
  17. Murray, P.J., Wang, L., Onufryk, C., Tepper, R.I., and Young, R.A. (1997). T cell-derived IL-10 antagonizes macrophage function in mycobacterial infection. J. Immunol. 158, 315–321.PubMedGoogle Scholar
  18. Nagalakshmi, M.L., Murphy, E., McClanahan, T., and de Waal Malefyt, R. (2004). Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization. Int. Immunopharmacol. 4, 577–592.PubMedCrossRefGoogle Scholar
  19. Nandi, D., Gross, J.A., and Allison, J.P. (1994). CD28-mediated costimulation is necessary for optimal proliferation of murine NK cells. J. Immunol. 152, 3361–3369.PubMedGoogle Scholar
  20. Neyer, L.E., Grunig, G., Fort, M., Remington, J.S., Rennick, D., and Hunter, C.A. (1997). Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii. Infect. Immun. 65, 1675–1682.PubMedGoogle Scholar
  21. Ortaldo, J.R., and Longo, D.L. (1988). Human natural lymphocyte effector cells: definition, analysis of activity, and clinical effectiveness. J. Natl. Cancer Inst. 80, 999–1010.PubMedCrossRefGoogle Scholar
  22. Pillet, A.H., Bugault, F., Theze, J., Chakrabarti, L.A., and Rose, T. (2009). A programmed switch from IL-15- to IL-2-dependent activation in human NK cells. J. Immunol. 182, 6267–6277.PubMedCrossRefGoogle Scholar
  23. Scharton, T.M., and Scott, P. (1993). Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178, 567–577.PubMedCrossRefGoogle Scholar
  24. Scharton-Kersten, T.M., and Sher, A. (1997). Role of natural killer cells in innate resistance to protozoan infections. Curr. Opin. Immunol. 9, 44–51.PubMedCrossRefGoogle Scholar
  25. Schulz, U., Kreutz, M., Multhoff, G., Stoelcker, B., Kohler, M., Andreesen, R., and Holler, E. (2010). Interleukin-10 promotes NK cell killing of autologous macrophages by stimulating expression of NKG2D ligands. Scand. J. Immunol. 72, 319–331.PubMedCrossRefGoogle Scholar
  26. Spits, H., Lanier, L.L., and Phillips, J.H. (1995) Development of human T and natural killer cells. Blood 85, 2654–2670.PubMedGoogle Scholar
  27. Sun, R., Fan, J., Wei, H., Zhang, C., and Tian, Z. (2003) Use of interleukin-15 for preparation of adherent NK cells from human peripheral blood: comparison with interleukin-2. J. Immunol. Methods 279, 79–90.PubMedCrossRefGoogle Scholar
  28. Tripp, C.S., Wolf, S.F., and Unanue, E.R. (1993) Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunode ficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc. Natl. Acad. Sci. USA 90, 3725–3729.PubMedCrossRefGoogle Scholar
  29. Waldmann, T.A. (2006). The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6, 595–601.PubMedCrossRefGoogle Scholar
  30. Waldmann, T.A., Dubois, S., and Tagaya, Y. (2001). Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14, 105–110.PubMedGoogle Scholar
  31. Weber-Nordt, R.M., Riley, J.K., Greenlund, A.C., Moore, K.W., Darnell, J.E., and Schreiber, R.D. (1996). Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J. Biol. Chem. 271, 27954–27961.PubMedCrossRefGoogle Scholar
  32. Yang, A.S., and Lattime, E.C. (2003). Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res. 63, 2150–2157.PubMedGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2011

Authors and Affiliations

  • Ju Yeong Park
    • 1
    • 2
  • Suk Hyung Lee
    • 1
  • Suk-Ran Yoon
    • 1
    • 2
  • Young-Jun Park
    • 1
    • 2
  • Haiyoung Jung
    • 1
    • 2
  • Tae-Don Kim
    • 1
    Email author
  • Inpyo Choi
    • 1
    • 2
    Email author
  1. 1.Cell Therapy Research CenterKorea Research Institute of Bioscience and BiotechnologyDaejeonKorea
  2. 2.Department of Functional GenomicsUniversity of Science and TechnologyDaejeonKorea

Personalised recommendations