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Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand

Nature Medicine volume 4, pages 1287–1292 (1998)Cite this article

Abstract

Fas ligand is a well-characterized apoptosis inducer. Here we demonstrate that Fas ligand induces the processing and secretion of interleukin-1β (IL-1β) in peritoneal exudate cells. This IL-1β secretion is independent of IL-1β converting enzyme (caspase 1), yet it is inhibited by caspase inhibitors, indicating that a caspase(s) in addition to IL-1β converting enzyme can process IL-1β. Inoculation of tumor cells expressing Fas ligand into wild-type mice induces a massive neutrophil infiltration that is, in contrast, suppressed in IL-1α/β knockout mice. These results demonstrate a newly discovered role for Fas ligand in inflammation, and challenge the dogma that apoptosis does not induce inflammation.

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Figure 1: Induction of neutrophil infiltration by MAFL.
Figure 2: Induction of IL-1β release and apoptosis by FasL and staurosporine.
Figure 3: Induction of IL-1β processing by FasL and staurosporine.
Figure 4: IL-1 processing and release in 4-h PEC can be independent of ICE, yet inhibited by caspase inhibitors.
Figure 5: Neutrophil infiltration is induced by MAFL in ICE KO mice, but not in IL-1 KO mice.

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References

  1. Suda, T., Takahashi, T., Golstein, P. & Nagata, S. Molecular cloning and expression of the Fas ligand: a novel member of the tumor necrosis factor family. Cell 75, 1169 –1178 (1993).

    Article  CAS  Google Scholar 

  2. Suda, T. et al. Expression of the Fas ligand in cells of T cell lineage. J. Immunol. 154, 3806–3813 (1995).

    CAS  PubMed  Google Scholar 

  3. Rouvier, E., Luciani, M.-F. & Golstein, P. Fas involvement in Ca2+-independent T cell-mediated cytotoxicity. J. Exp. Med. 177, 195–200 (1993).

    Article  CAS  Google Scholar 

  4. Arase, H., Arase, N. & Saito, T. Fas-mediated cytotoxicity by freshly isolated natural killer cells. J. Exp. Med. 181, 1235– 1238 (1995).

    Article  CAS  Google Scholar 

  5. Suda, T. & Nagata, S. Why do defects in the Fas-Fas ligand system cause autoimmunity? J. Allergy Clin. Immunol. 100, S97–101 (1997).

    Article  CAS  Google Scholar 

  6. Nagata, S. & Suda, T. Fas and Fas ligand: lpr and gld mutations. Immunol. Today 16, 39 –43 (1995).

    Article  CAS  Google Scholar 

  7. Barker, C.F. & Billingham, R.E. Immunologically privileged sites. Adv. Immunol. 25, 1– 54 (1977).

    CAS  PubMed  Google Scholar 

  8. Bellgrau, D. et al. A role for CD95 ligand in preventing graft rejection. Nature 377, 630–632 ( 1995).

    Article  CAS  Google Scholar 

  9. Griffith, T.S., Brunner, T., Fletcher, S.M., Green, D.R. & Ferguson, T.A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).

    Article  CAS  Google Scholar 

  10. Lau, H.T., Yu, M., Fontana, A. & Stoeckert, C.J. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273, 109– 112 (1996).

    Article  CAS  Google Scholar 

  11. Kang, S.M. et al. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nature Med. 3, 738–743 ( 1997).

    Article  CAS  Google Scholar 

  12. Allison, J., Georgiou, H.M., Strasser, A. & Vaux, D.L. Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc. Natl. Acad. Sci. U S A 94, 3943– 3947 (1997).

    Article  CAS  Google Scholar 

  13. O'Connell, J., O'Sullivan, G.C., Collins, J.K. & Shanahan, F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J. Exp. Med. 184, 1075– 1082 (1996).

    Article  CAS  Google Scholar 

  14. Hahne, M. et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274, 1363 –1366 (1996).

    Article  CAS  Google Scholar 

  15. Niehans, G.A. et al. Human lung carcinomas express Fas ligand. Cancer Res. 57, 1007–1012 ( 1997).

    CAS  PubMed  Google Scholar 

  16. Seino, K., Kayagaki, N., Okumura, K. & Yagita, H. Antitumor effect of locally produced CD95 ligand. Nat Med 3, 165–170 (1997).

    Article  CAS  Google Scholar 

  17. Tanaka, M., Suda, T., Takahashi, T. & Nagata, S. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J. 14, 1129–1135 ( 1995).

    Article  CAS  Google Scholar 

  18. Kayagaki, N. et al. Metalloproteinase-mediated release of human Fas ligand. J. Exp. Med. 182, 1777–1783 (1995).

    Article  CAS  Google Scholar 

  19. Mariani, S.M., Matiba, B., Baumler, C. & Krammer, P.H. Regulation of cell surface APO-1/Fas (CD95) ligand expression by metalloproteases. Eur. J. Immunol. 25, 2303–2307 (1995).

    Article  CAS  Google Scholar 

  20. Suda, T., Hashimoto, H., Tanaka, M., Ochi, T. & Nagata, S. Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J. Exp. Med. 186, 2045–2050 (1997).

    Article  CAS  Google Scholar 

  21. Tanaka, M., Itai, T., Adachi, M. & Nagata, S. Downregulation of Fas ligand by shedding. Nature Med. 4, 31–36 (1998).

    Article  CAS  Google Scholar 

  22. Sayers, T.J. et al. Effect of cytokines on polymorphonuclear neutrophil infiltration in the mouse. Prostaglandin- and leukotriene-independent induction of infiltration by IL-1 and tumor necrosis factor. J. Immunol. 141, 1670–1677 (1988).

    CAS  PubMed  Google Scholar 

  23. Suda, T., Tanaka, M., Miwa, K. & Nagata, S. Apoptosis of mouse naive T cells induced by recombinant soluble Fas ligand and activation-induced resistance to Fas ligand. J. Immunol. 157, 3918–3924 (1996).

    CAS  PubMed  Google Scholar 

  24. Iwai, K. et al. Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils. Blood 84, 1201–1208 ( 1994).

    CAS  PubMed  Google Scholar 

  25. Liles, W.C., Kiener, P.A., Ledbetter, J.A., Aruffo, A. & Klebanoff, S.J. Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils. J. Exp. Med. 184, 429–440 (1996).

    Article  CAS  Google Scholar 

  26. Li, P. et al. Mice deficient in IL-1 β-converting enzyme are defective in production of mature IL-1 β and resistant to endotoxic shock. Cell 80, 401–411 ( 1995).

    Article  CAS  Google Scholar 

  27. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin- 1 β converting enzyme. Science 267 , 2000–2003 (1995).

    Article  CAS  Google Scholar 

  28. Irmler, M. et al. Granzyme A is an interleukin 1 β-converting enzyme. J. Exp. Med. 181, 1917– 1922 (1995).

    Article  CAS  Google Scholar 

  29. Mizutani, H., Schechter, N., Lazarus, G., Black, R.A. & Kupper, T.S. Rapid and specific conversion of precursor interleukin 1 β (IL-1 β) to an active IL-1 species by human mast cell chymase. J. Exp. Med. 174, 821–825 (1991).

    Article  CAS  Google Scholar 

  30. Lindemann, A. et al. Granulocyte/macrophage colony-stimulating factor induces interleukin 1 production by human polymorphonuclear neutrophils. J. Immunol. 140, 837–839 (1988).

    CAS  PubMed  Google Scholar 

  31. Parsey, M.V., Tuder, R.M. & Abraham, E. Neutrophils are major contributors to intraparenchymal lung IL-1 β expression after hemorrhage and endotoxemia. J. Immunol. 160, 1007–1013 (1998).

    CAS  PubMed  Google Scholar 

  32. Hogquist, K.A., Nett, M.A., Unanue, E.R. & Chaplin, D.D. Interleukin 1 is processed and released during apoptosis. Proc. Natl. Acad. Sci. USA 88, 8485–8489 ( 1991).

    Article  CAS  Google Scholar 

  33. Fantuzzi, G. et al. Effect of endotoxin in IL-1 beta-deficient mice. J. Immunol. 157, 291–296 (1996).

    CAS  PubMed  Google Scholar 

  34. Colotta, F., Re, F., Polentarutti, N., Sozzani, S. & Mantovani, A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 80 , 2012–2020 (1992).

    CAS  PubMed  Google Scholar 

  35. Ghayur, T. et al. Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN-γ production. Nature 386, 619–623 (1997).

    Article  CAS  Google Scholar 

  36. Kondo, T., Suda, T., Fukuyama, H., Adachi, M. & Nagata, S. Essential roles of the Fas ligand in the development of hepatitis. Nature Med. 3, 409– 413 (1997).

    Article  CAS  Google Scholar 

  37. Nakamoto, Y., Guidotti, L.G., Pasquetto, V., Schreiber, R.D. & Chisari, F.V. Differential target cell sensitivity to CTL-activated death pathways in hepatitis B virus transgenic mice. J. Immunol. 158, 5692–5697 (1997).

    CAS  PubMed  Google Scholar 

  38. Giordano, C. et al. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 275, 960–963 (1997).

    Article  CAS  Google Scholar 

  39. Jaffe, G.J. et al. Expression of interleukin-1 α, interleukin-1 β, and an interleukin-1 receptor antagonist in human retinal pigment epithelial cells. Exp. Eye Res. 55, 325– 335 (1992).

    Article  CAS  Google Scholar 

  40. de Vos, A.F., Klaren, V.N. & Kijlstra, A. Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Invest. Ophthalmol. Vis. Sci. 35, 3873– 3883 (1994).

    CAS  PubMed  Google Scholar 

  41. Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL- 1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463– 1475 (1998).

    Article  CAS  Google Scholar 

  42. Mizushima, S. & Nagata, S. pEF-BOS: a powerful mammalian expression vector. Nucleic Acids Res. 18, 5322 (1990).

    Article  CAS  Google Scholar 

  43. Suda, T. & Nagata, S. Purification and characterization of the Fas ligand that induces apoptosis. J. Exp. Med. 179, 873–878 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Suda and R. Hayashi for secretarial assistance. This work was supported in part by grants-in-aid from the Ministry of Education, Science and Culture of Japan, and by Special Coordination Funds of Science and Technology Agency of the Japanese Government.

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Authors and Affiliations

  1. Department of Molecular Biology, Osaka Bioscience Institute, Suita, 565-0874, Osaka, Japan

    Keiko Miwa, Shigekazu Nagata & Takashi Suda

  2. The University of Tokyo, The Institute of Medical Science, Laboratory Animal Research Center, Minato-ku, 108-8639, Tokyo, Japan

    Masahide Asano, Reiko Horai & Yoichiro Iwakura

  3. Department of Genetics, Osaka University Medical School, Suita, 565-0871, Osaka, Japan

    Shigekazu Nagata

  4. Kanazawa University, Cancer Research Institute, Center for the Development of Molecular Target Drugs, Kanazawa, 920-0934, Ishikawa, Japan

    Takashi Suda

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Correspondence to Takashi Suda.

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Miwa, K., Asano, M., Horai, R. et al. Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand. Nat Med 4, 1287–1292 (1998). https://doi.org/10.1038/3276

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