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. 1999 Jun 1;18(11):3034–3043. doi: 10.1093/emboj/18.11.3034

Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF.

M Grell 1, G Zimmermann 1, E Gottfried 1, C M Chen 1, U Grünwald 1, D C Huang 1, Y H Wu Lee 1, H Dürkop 1, H Engelmann 1, P Scheurich 1, H Wajant 1, A Strasser 1
PMCID: PMC1171385  PMID: 10357816

Abstract

Several members of the tumour necrosis factor receptor (TNF-R) superfamily can induce cell death. For TNF-R1, Fas/APO-1, DR3, DR6, TRAIL-R1 and TRAIL-R2, a conserved 'death domain' in the intracellular region couples these receptors to activation of caspases. However, it is not yet known how TNF receptor family members lacking a death domain, such as TNF-R2, CD40, LT-betaR, CD27 or CD30, execute their death-inducing capability. Here we demonstrate in different cellular systems that cytotoxic effects induced by TNF-R2, CD40 and CD30 are mediated by endogenous production of TNF and autotropic or paratropic activation of TNF-R1. In addition, stimulation of TNF-R2 and CD40 synergistically enhances TNF-R1-induced cytotoxicity. These findings describe a novel pro-apoptotic mechanism induced by some members of the TNF-R family.

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Selected References

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  1. Afford S. C., Randhawa S., Eliopoulos A. G., Hubscher S. G., Young L. S., Adams D. H. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med. 1999 Jan 18;189(2):441–446. doi: 10.1084/jem.189.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander-Miller M. A., Derby M. A., Sarin A., Henkart P. A., Berzofsky J. A. Supraoptimal peptide-major histocompatibility complex causes a decrease in bc1-2 levels and allows tumor necrosis factor alpha receptor II-mediated apoptosis of cytotoxic T lymphocytes. J Exp Med. 1998 Oct 19;188(8):1391–1399. doi: 10.1084/jem.188.8.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amakawa R., Hakem A., Kundig T. M., Matsuyama T., Simard J. J., Timms E., Wakeham A., Mittruecker H. W., Griesser H., Takimoto H. Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice. Cell. 1996 Feb 23;84(4):551–562. doi: 10.1016/s0092-8674(00)81031-4. [DOI] [PubMed] [Google Scholar]
  4. Arch R. H., Gedrich R. W., Thompson C. B. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. Genes Dev. 1998 Sep 15;12(18):2821–2830. doi: 10.1101/gad.12.18.2821. [DOI] [PubMed] [Google Scholar]
  5. Ashkenazi A., Dixit V. M. Death receptors: signaling and modulation. Science. 1998 Aug 28;281(5381):1305–1308. doi: 10.1126/science.281.5381.1305. [DOI] [PubMed] [Google Scholar]
  6. Black R. A., Rauch C. T., Kozlosky C. J., Peschon J. J., Slack J. L., Wolfson M. F., Castner B. J., Stocking K. L., Reddy P., Srinivasan S. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729–733. doi: 10.1038/385729a0. [DOI] [PubMed] [Google Scholar]
  7. Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
  8. Boldin M. P., Mett I. L., Varfolomeev E. E., Chumakov I., Shemer-Avni Y., Camonis J. H., Wallach D. Self-association of the "death domains" of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Biol Chem. 1995 Jan 6;270(1):387–391. doi: 10.1074/jbc.270.1.387. [DOI] [PubMed] [Google Scholar]
  9. Brockhaus M., Schoenfeld H. J., Schlaeger E. J., Hunziker W., Lesslauer W., Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127–3131. doi: 10.1073/pnas.87.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Browning J. L., Miatkowski K., Sizing I., Griffiths D., Zafari M., Benjamin C. D., Meier W., Mackay F. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med. 1996 Mar 1;183(3):867–878. doi: 10.1084/jem.183.3.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Clark E. A., Ledbetter J. A. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4494–4498. doi: 10.1073/pnas.83.12.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Duckett C. S., Thompson C. B. CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev. 1997 Nov 1;11(21):2810–2821. doi: 10.1101/gad.11.21.2810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eissner G., Kohlhuber F., Grell M., Ueffing M., Scheurich P., Hieke A., Multhoff G., Bornkamm G. W., Holler E. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood. 1995 Dec 1;86(11):4184–4193. [PubMed] [Google Scholar]
  14. Eliopoulos A. G., Dawson C. W., Mosialos G., Floettmann J. E., Rowe M., Armitage R. J., Dawson J., Zapata J. M., Kerr D. J., Wakelam M. J. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator. Oncogene. 1996 Nov 21;13(10):2243–2254. [PubMed] [Google Scholar]
  15. Fischer P., Nacheva E., Mason D. Y., Sherrington P. D., Hoyle C., Hayhoe F. G., Karpas A. A Ki-1 (CD30)-positive human cell line (Karpas 299) established from a high-grade non-Hodgkin's lymphoma, showing a 2;5 translocation and rearrangement of the T-cell receptor beta-chain gene. Blood. 1988 Jul;72(1):234–240. [PubMed] [Google Scholar]
  16. Grell M., Douni E., Wajant H., Löhden M., Clauss M., Maxeiner B., Georgopoulos S., Lesslauer W., Kollias G., Pfizenmaier K. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995 Dec 1;83(5):793–802. doi: 10.1016/0092-8674(95)90192-2. [DOI] [PubMed] [Google Scholar]
  17. Grell M., Scheurich P., Meager A., Pfizenmaier K. TR60 and TR80 tumor necrosis factor (TNF)-receptors can independently mediate cytolysis. Lymphokine Cytokine Res. 1993 Jun;12(3):143–148. [PubMed] [Google Scholar]
  18. Grell M., Zimmermann G., Hülser D., Pfizenmaier K., Scheurich P. TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways. J Immunol. 1994 Sep 1;153(5):1963–1972. [PubMed] [Google Scholar]
  19. Gross A., Yin X. M., Wang K., Wei M. C., Jockel J., Milliman C., Erdjument-Bromage H., Tempst P., Korsmeyer S. J. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem. 1999 Jan 8;274(2):1156–1163. doi: 10.1074/jbc.274.2.1156. [DOI] [PubMed] [Google Scholar]
  20. Haridas V., Darnay B. G., Natarajan K., Heller R., Aggarwal B. B. Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Jun kinase activation. J Immunol. 1998 Apr 1;160(7):3152–3162. [PubMed] [Google Scholar]
  21. Heller R. A., Song K., Fan N., Chang D. J. The p70 tumor necrosis factor receptor mediates cytotoxicity. Cell. 1992 Jul 10;70(1):47–56. doi: 10.1016/0092-8674(92)90532-h. [DOI] [PubMed] [Google Scholar]
  22. Hess S., Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J Exp Med. 1996 Jan 1;183(1):159–167. doi: 10.1084/jem.183.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Huang D. C., Cory S., Strasser A. Bcl-2, Bcl-XL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. Oncogene. 1997 Jan 30;14(4):405–414. doi: 10.1038/sj.onc.1200848. [DOI] [PubMed] [Google Scholar]
  24. Itoh N., Nagata S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem. 1993 May 25;268(15):10932–10937. [PubMed] [Google Scholar]
  25. Jacobson M. D., Weil M., Raff M. C. Programmed cell death in animal development. Cell. 1997 Feb 7;88(3):347–354. doi: 10.1016/s0092-8674(00)81873-5. [DOI] [PubMed] [Google Scholar]
  26. Jongeneel C. V. Transcriptional regulation of the tumor necrosis factor alpha gene. Immunobiology. 1995 Jul;193(2-4):210–216. doi: 10.1016/s0171-2985(11)80545-0. [DOI] [PubMed] [Google Scholar]
  27. Kasibhatla S., Brunner T., Genestier L., Echeverri F., Mahboubi A., Green D. R. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell. 1998 Mar;1(4):543–551. doi: 10.1016/s1097-2765(00)80054-4. [DOI] [PubMed] [Google Scholar]
  28. Kischkel F. C., Hellbardt S., Behrmann I., Germer M., Pawlita M., Krammer P. H., Peter M. E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995 Nov 15;14(22):5579–5588. doi: 10.1002/j.1460-2075.1995.tb00245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lee S. Y., Park C. G., Choi Y. T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors. J Exp Med. 1996 Feb 1;183(2):669–674. doi: 10.1084/jem.183.2.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Li H., Zhu H., Xu C. J., Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998 Aug 21;94(4):491–501. doi: 10.1016/s0092-8674(00)81590-1. [DOI] [PubMed] [Google Scholar]
  31. Luo X., Budihardjo I., Zou H., Slaughter C., Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998 Aug 21;94(4):481–490. doi: 10.1016/s0092-8674(00)81589-5. [DOI] [PubMed] [Google Scholar]
  32. McCarthy J. V., Ni J., Dixit V. M. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem. 1998 Jul 3;273(27):16968–16975. doi: 10.1074/jbc.273.27.16968. [DOI] [PubMed] [Google Scholar]
  33. Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. doi: 10.1016/s0092-8674(00)81874-7. [DOI] [PubMed] [Google Scholar]
  34. Sarin A., Conan-Cibotti M., Henkart P. A. Cytotoxic effect of TNF and lymphotoxin on T lymphoblasts. J Immunol. 1995 Oct 15;155(8):3716–3718. [PubMed] [Google Scholar]
  35. Scaffidi C., Fulda S., Srinivasan A., Friesen C., Li F., Tomaselli K. J., Debatin K. M., Krammer P. H., Peter M. E. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998 Mar 16;17(6):1675–1687. doi: 10.1093/emboj/17.6.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schneider P., Holler N., Bodmer J. L., Hahne M., Frei K., Fontana A., Tschopp J. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med. 1998 Apr 20;187(8):1205–1213. doi: 10.1084/jem.187.8.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schwab U., Stein H., Gerdes J., Lemke H., Kirchner H., Schaadt M., Diehl V. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature. 1982 Sep 2;299(5878):65–67. doi: 10.1038/299065a0. [DOI] [PubMed] [Google Scholar]
  38. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  39. Smith C. A., Gruss H. J., Davis T., Anderson D., Farrah T., Baker E., Sutherland G. R., Brannan C. I., Copeland N. G., Jenkins N. A. CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell. 1993 Jul 2;73(7):1349–1360. doi: 10.1016/0092-8674(93)90361-s. [DOI] [PubMed] [Google Scholar]
  40. Smith K. G., Strasser A., Vaux D. L. CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J. 1996 Oct 1;15(19):5167–5176. [PMC free article] [PubMed] [Google Scholar]
  41. Speiser D. E., Sebzda E., Ohteki T., Bachmann M. F., Pfeffer K., Mak T. W., Ohashi P. S. Tumor necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo. Eur J Immunol. 1996 Dec;26(12):3055–3060. doi: 10.1002/eji.1830261235. [DOI] [PubMed] [Google Scholar]
  42. Stein H., Mason D. Y., Gerdes J., O'Connor N., Wainscoat J., Pallesen G., Gatter K., Falini B., Delsol G., Lemke H. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985 Oct;66(4):848–858. [PubMed] [Google Scholar]
  43. Strasser A., Harris A. W., Huang D. C., Krammer P. H., Cory S. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J. 1995 Dec 15;14(24):6136–6147. doi: 10.1002/j.1460-2075.1995.tb00304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Strasser A. Life and death during lymphocyte development and function: evidence for two distinct killing mechanisms. Curr Opin Immunol. 1995 Apr;7(2):228–234. doi: 10.1016/0952-7915(95)80007-7. [DOI] [PubMed] [Google Scholar]
  45. Strasser A., O'Connor L. Fas ligand--caught between Scylla and Charybdis. Nat Med. 1998 Jan;4(1):21–22. doi: 10.1038/nm0198-021. [DOI] [PubMed] [Google Scholar]
  46. Swantek J. L., Cobb M. H., Geppert T. D. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Mol Cell Biol. 1997 Nov;17(11):6274–6282. doi: 10.1128/mcb.17.11.6274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tanaka M., Itai T., Adachi M., Nagata S. Downregulation of Fas ligand by shedding. Nat Med. 1998 Jan;4(1):31–36. doi: 10.1038/nm0198-031. [DOI] [PubMed] [Google Scholar]
  48. Tartaglia L. A., Ayres T. M., Wong G. H., Goeddel D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993 Sep 10;74(5):845–853. doi: 10.1016/0092-8674(93)90464-2. [DOI] [PubMed] [Google Scholar]
  49. Thoma B., Grell M., Pfizenmaier K., Scheurich P. Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med. 1990 Oct 1;172(4):1019–1023. doi: 10.1084/jem.172.4.1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Thornberry N. A., Lazebnik Y. Caspases: enemies within. Science. 1998 Aug 28;281(5381):1312–1316. doi: 10.1126/science.281.5381.1312. [DOI] [PubMed] [Google Scholar]
  51. Thornberry N. A., Rano T. A., Peterson E. P., Rasper D. M., Timkey T., Garcia-Calvo M., Houtzager V. M., Nordstrom P. A., Roy S., Vaillancourt J. P. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem. 1997 Jul 18;272(29):17907–17911. doi: 10.1074/jbc.272.29.17907. [DOI] [PubMed] [Google Scholar]
  52. VanArsdale T. L., VanArsdale S. L., Force W. R., Walter B. N., Mosialos G., Kieff E., Reed J. C., Ware C. F. Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2460–2465. doi: 10.1073/pnas.94.6.2460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Vandenabeele P., Declercq W., Vanhaesebroeck B., Grooten J., Fiers W. Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells. J Immunol. 1995 Mar 15;154(6):2904–2913. [PubMed] [Google Scholar]
  54. Varfolomeev E. E., Boldin M. P., Goncharov T. M., Wallach D. A potential mechanism of "cross-talk" between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other. J Exp Med. 1996 Mar 1;183(3):1271–1275. doi: 10.1084/jem.183.3.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Vercammen D., Vandenabeele P., Declercq W., Van de Craen M., Grooten J., Fiers W. Cytotoxicity in L929 murine fibrosarcoma cells after triggering of transfected human p75 tumour necrosis factor (TNF) receptor is mediated by endogenous murine TNF. Cytokine. 1995 Jul;7(5):463–470. doi: 10.1006/cyto.1995.0063. [DOI] [PubMed] [Google Scholar]
  56. Weiss T., Grell M., Hessabi B., Bourteele S., Müller G., Scheurich P., Wajant H. Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site. J Immunol. 1997 Mar 1;158(5):2398–2404. [PubMed] [Google Scholar]
  57. Weiss T., Grell M., Siemienski K., Mühlenbeck F., Dürkop H., Pfizenmaier K., Scheurich P., Wajant H. TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J Immunol. 1998 Sep 15;161(6):3136–3142. [PubMed] [Google Scholar]
  58. Zheng L., Fisher G., Miller R. E., Peschon J., Lynch D. H., Lenardo M. J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. doi: 10.1038/377348a0. [DOI] [PubMed] [Google Scholar]
  59. Zhou T., Edwards C. K., 3rd, Yang P., Wang Z., Bluethmann H., Mountz J. D. Greatly accelerated lymphadenopathy and autoimmune disease in lpr mice lacking tumor necrosis factor receptor I. J Immunol. 1996 Apr 15;156(8):2661–2665. [PubMed] [Google Scholar]

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