Cytokine Synergism in Apoptosis: Its Role in Diabetes and Cancer

  • Lee, Myung-Shik (Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine and National Research Laboratory of Cell Death and Diabetes Research)
  • Published : 2002.01.31


The effects of individual cytokine on apoptosis have been extensively studied. However, the effect of the cytokine combination, or the synergistic effect of cytokines on cell death, has not been widely studied, though synergism between cytokines has been documented in a variety of biological situations. In our effort to identify the final death effector molecule(s) in autoimmune diabetes, we inadvertently became interested in the cytokine synergism. We discovered that $IFN{\gamma}/TNF{\alpha}$ synergism, rather than the Fas ligand as currently believed, is responsible for the apoptosis of pancreatic islet cells both in vitro and in vivo. We also studied similar cytokine synergism in cancer cell deaths, and noted the similarities and dissimilarities between cancer cell death and islet cell death.


  1. Amrani, A., Verdaguer, J., Anderson, B., Utsugi, T., Bou, S. and Santamaria, P. (1999) Perforin-independent $\beta$-cell destruction by diabetogenic CD8+ T lymphocytes in transgenic nonobese diabetic mice. J Clin. Invest. 103, 1201-1209.
  2. Chervonsky, A. V., Wang, Y., Wong, F. S., Visintin, I., Flavell, R. A., Janeway, C. A. and Matis, L. A. (1997) The role of Fas in autoimmune diabetes. Cell 89, 17-24.
  3. Chu, J. L., Ramos, P., Rosendorff, A., Nikolic-Zugic, J., Lacy, E., Matsuzawa, A. and Elkon, K. B. (1995) Massive upregulation of the Fas ligand in Ipr and gld mice: Implications for Fas regulation and the graft-versus-host disease-like wasting syndrome. J. Exp. Med. 181, 393-398.
  4. Enari, M., Talanian, R. V., Wong, W. W. and Nagata, S. (1996) Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature 380, 723-726.
  5. Fransen, L., Heyden, J., Ruysschaert, R. and Fiers, W. (1986) Recombinant tumor necrosis factor: its effect and its synergism with interferon-$\gamma$ on a variety of normal and transformed human cell lines. Br. J. Cancer Clin. Oncol. 22,419-426.
  6. Haskins, K. and McDuffie, M. (1990) Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249, 1433-1436.
  7. Hayashi, T. and Faustrnan, D. (1999) NOD mice are defective in proteasome production and activation of $NF-{\kappa}B$. Mol. Cell. BioI. 19, 8648-8659.
  8. Henkart, P. A. (1994) Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity 1, 343- 346.
  9. Hisahara, M., Shoji, S., Okano, H. and Miura, M. (1997) ICE/ CED-3 family executes oligodendrocyte apoptosis by tumor necrosis factor. J. Neurochem. 69, 10-20.
  10. Itoh, N., Imagawa, A., Hanafusa, T., Waguri, M., Yamamoto, K., Iwasashi, H., Moriwaki, M., Nakajima, H., Miyagawa, M., Namba, M., et al. (1997) Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J. Exp. Med. 186,613-618.
  11. Ju, S.-T., Cui, H., Panka, D. J., Ettinger, R. and A., M.-R. (1994) Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc. Natl. Acad. Sci. USA 91, 4185-4189.
  12. Kagi, D., Odermatt, B., Ohashi, P. S., Zinkernagel, R. M. and Hengartner, H. (1996) Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J Exp. Med. 183, 2143-2152.
  13. Kagi, D., Odermatt, B., Seiler, P., Zinkemagel, R. M., Mak, T. W. and Hengartner, H. (1997) Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J. Exp. Med. 186, 989-997.
  14. Kagi, D., Vignaux, F., Ledermann, B., Burki, K., Depraetere, V., Nagata, S., Hengartner, H. and Golstein, P. (1994) Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265, 528-530.
  15. Kang, S. J., Wang, S., Hara, H., Peterson, E. P., Namura, S., Arnin-Hanjani, S., Huang, Z., Srinivasan, A., Tomaselli, K. J., Thornberry, N. A., Moskowitz, M. A. and Yuan, J. (2000) Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological condition. J. Cell BioI. 149, 613- 622.
  16. Kano, A., Haruyama, T., Akaike, T. and Watanabe, Y. (1999). IRF-1 is an essential mediator in IFN--${\gamma}$-induced cell cycle arrest and apoptosis in primary cultured hepatocytes. Biochem. Biophys. Res. Com. 257,672-677.
  17. Kim, S., Kim, J. Y., Lee, T. H., Suk, K., Cha, H.-S., Koh, E.-M., Yagita, H. and Lee, M.-S. Soluble Fas Ligand-Susceptible 'Memory' Cells in Mice but Not in Human: Potential role of soluble Fas ligand in deletion of autoreactive cells. Autoimmunity, in press.
  18. Kim, S., Kim, K.-A., Hwang, D.-Y., Lee, T. H., Kayagaki, N., Yagita, H. and Lee, M.-S. (2000) Inhibition of autoimmune diabetes by Fas ligand: the paradox is solved. J. Immunol. 164, 2931-2936.
  19. Kim, Y-H., Kim, S., Kim, K.-A., Yagita, H., Kayagaki, N., Kim, K.-W. and Lee, M.-S. (1999) Apoptosis of pancreatic ${\beta}$-cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes. Eur. J Immunol. 29, 455-465.<455::AID-IMMU455>3.0.CO;2-A
  20. Kontny, H. U., Hammerle, K., Klein, R., Shayan, P., Mackall, C. L. and Niemeyer, C. M. (2001) Sensitivity of Ewing's sarcoma to TRAIL-induced apoptosis. Cell Death Differ. 8, 505-514.
  21. Kumar, A., Commane, M., Flickinger, T. W., Horvath, C. M. and Stark, G. R. (1997) Defective TNF-$\alpha$-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278, 1630-1632.
  22. Lee, M.-S., Kim, S., Chung, J. H., Lee, M.-K and Kim, K.-W. (1999) Fas is expressed in murine pancreatic islet cells and an insulinoma cell line but does not mediate their apoptosis in vitro. Autoimmunity 29, 189-199.
  23. Quirk, S. M., Porter, D. A., Huber, S. C. and Cowan, R. G. (1998) Potentiation of Fas-mediated apoptosis of murine granulosa cells by interferon-gamma, tumor necrosis factoralpha, and cycloheximide. Endocrinology 139, 4860-4869.
  24. Reap, E. A., Roof, K., Maynor, K., Borrero, M., Booker, J. and Cohen, P. L. (1997) Radiation and stress-induced apoptosis: A role for FaslFas ligand interaction. Proc. Natl. Acad. Sci. USA 94, 5750-5755.
  25. Suk, K., Kim, S., Kim, Y-H., Kim, K-A., Chang, I., Yagita, H.,Shong, M. and Lee, M.-S. (2001a) $IFN{\gamma}/TNF{\alpha}$ Synergism as the Final Effector in Autoimmune Diabetes: A key role for IRF-1 in pancreatic $\beta$-cell death. J. lmmunol. 166,4481-4489.
  26. Suk, K., Kim, Y. H., Chang, I., Kim, J. Y., Choi, Y. H., Lee, K. Y. and Lee, M. S. (2001b) IFNalpha sensitizes ME-180 human cervical cancer cells to TNFalpha-induced apoptosis by inhibiting cytoprotective NF-kappaB activation. FEBS Letters 495,66-70.
  27. Tamura, T., Ishihara, M., Lamphier, M. S., Tanaka, N., Oishi, I., Aizawa, S., Maatsuyama, T., Mak, T. W., Take, S. and Taniguchi, T. (1995) An IRF-l-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature 376, 596-599.
  28. Tanaka, M., Suda, T., Haze, K., Nakamura, N., Sato, K., Kimura, F., Motoyoshi, K., Mizuki, M., Tagawa, S., Ohga, S., et al. (1996) Fas ligand in human serum. Nat. Med. 2, 317-322.
  29. Wang, S., Miura, M., Jung, Y.-K., Zhu, H. and Yuan, J. (1998) Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501-509.
  30. Wang, Y., Pontesilli, O., Gill, R. D., La Rosa, F. G. and Lafferty, K. J. (1991) The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice. Proc. Natl. Acad. Sci. USA 88, 527-531.
  31. Watanabe, D., Suda, T., Hashimoto, H. and Nagata, S. (1995) Constitutive activation of the Fas ligand gene in mouse Iymphoproliferative disorders. EMBO J. 14, 12-18.
  32. Wicker, L. A., Miller, B. J. and Mullen, Y. (1986) Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes 35, 855-860.
  33. Wofsy, D., Hardy, R. R. and Seaman, W. (1984) The proliferating cells in autoimmune MRL/1pr mice lack L3T4, an antigen on "helper" T cells that is involved in the response to class II major histocompatibility antigens. J. lmmunol. 132, 2686-2689.
  34. Yamada, K., Takane-Gyotoku, N., Yuan, X., Ichikawa, F. and Nonaka, K. (1996) Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 39, 1306-1312.

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