Apoptosis and Autoimmune Diseases



Apoptosis plays critical roles in the initiation, progression and remission of autoimmune diseases. On the one hand, apotosis of resident tissue cells in diseased organs contributes to the pathology of autoimmune diseases. On the other hand, apoptosis of inflammatory cells is essential for disease recovery and is the major goal of therapeutic interventions for autoimmune diseases. In this review, I will discuss the roles of apoptosis in two common autoimmune diseases: multiple sclerosis and rheumatoid arthritis. I will also examine the potential roles of transcription factor p53 and the tumor necrosis factor family of proteins in autoimmune diseases.

Key Words

RA MS Fas TRAIL Transcription Factors TNF 


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  1. Abreu-Martin, M. T., Vidrich, A., Lynch, D. H., and Targan, S. R. (1995). Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-alpha and ligation of Fas antigen. Journal of Immunology 155, 4147–54.Google Scholar
  2. Abulencia, J. P., Gaspard, R., Quackenbush, J., and konstantopoulos, K. (2002). Discovery and characterization of differentially regulated genes in the chondrocytic cell line T/C-28a2 under dynamic fluid shear. FASEB Journal 16, A656. 7.Google Scholar
  3. Argiles, J. M., Lopez-Soriano, J., Busquets, S., and Lopez-Soriano, F. J. (1997). Journey from cachexia to obesity by TNF. Faseb J 11, 743–51.PubMedGoogle Scholar
  4. Arrowsmith, C. H. (1999). Structure and function in the p53 family. Cell Death and Differentiation 6, 1169–73.PubMedGoogle Scholar
  5. Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., Blackie, C., Chang, L., McMurtrey, A. E., Hebert, A., DeForge, L., Koumenis, I. L., Lewis, D., Harris, L., Bussiere, J., Koeppen, H., Shahrokh, Z., and Schwall, R. H. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. Journal of Clinical Investigation 104, 155–62.PubMedGoogle Scholar
  6. Baker, S. J., and Reddy, E. P. (1996). Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12, 1–9.PubMedGoogle Scholar
  7. Bennett, M., Macdonald, K., Chan, S. W., Luzio, J. P., Simari, R., and Weissberg, P. (1998). Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282, 290–3.PubMedGoogle Scholar
  8. Beutler, B., and Bazzoni, F. (1998). TNF, apoptosis and autoimmunity: a common thread? Blood Cells Mol Dis 24, 216–30.PubMedGoogle Scholar
  9. Bodmer, J. L., Holler, N., Reynard, S., Vinciguerra, P., Schneider, P., Juo, P., Blenis, J., and Tschopp, J. (2000). TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2, 241–3.Google Scholar
  10. Brennan, F. M., Maini, R. N., and Feldmann, M. (1995). Cytokine expression in chronic inflammatory disease.Google Scholar
  11. British Medical Bulletin 51,368–84.Google Scholar
  12. Buckbinder, L., Talbott, R., Velasco-Miguel, S., Takenaka, I., Faha, B., Seizinger, B. R., and Kley, N. (1995). Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377, 646–9.PubMedGoogle Scholar
  13. Burns, T. F., and El-Deiry, W. S. (1999). The p53 pathway and apoptosis. Journal of Cellular Physiology 181, 231–9.PubMedGoogle Scholar
  14. Chaudhary, P. M., Eby, M., Jasmin, A., Bookwalter, A., Murray, J., and Hood, L. (1997). Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 7, 821–30.PubMedGoogle Scholar
  15. Chen, Y., Hancock, W. W., Marks, R., Gonnella, P., and Weiner, H. L. (1998). Mechanisms of recovery from experimental autoimmune encephalomyelitis: T cell deletion and immune deviation in myelin basic protein T cell receptor transgenic mice. Journal of Neuroimmunology 82, 149–59.PubMedGoogle Scholar
  16. Chen, Y., Kuchroo, V. K., Inobe, J.-I., Hafler, D. A., and Weiner, H. L. (1994). Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240.PubMedGoogle Scholar
  17. Chervonsky, A. V., Wang, Y., Wong, F. S., Visintin, I., Flavell, R. A., Janeway, C. A., Jr., and Matis, L. A. (1997). The role of Fas in autoimmune diabetes. Cell 89, 17–24.Google Scholar
  18. Chou, C. T., Yang, J. S., and Lee, M. R. (2001). Apoptosis in rheumatoid arthritis—expression of Fas, Fas-L, p53, and Bcl-2 in rheumatoid synovial tissues. Journal of Pathology 193, 110–6.PubMedGoogle Scholar
  19. Cohen, P. L., and Eisenberg, R. A. (1992). The 1pr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunology Today 13, 427–8.PubMedGoogle Scholar
  20. Cutolo, M., Sulli, A., Barone, A., Seriolo, B., and Accardo, S. (1993). Macrophages, synovial tissue and rheumatoid arthritis. Clinical and Experimental Rheumatology 11, 331–9.Google Scholar
  21. D’Souza, S. D., Bonetti, B., Balasingam, V., Cashman, N. R., Barker, P. A., Troutt, A. B., Raine, C. S., and Antel, J. P. (1996). Multiple sclerosis: Fas signaling in oligodendrocyte cell death. Journal of Experimental Medicine 184, 2361–70.PubMedGoogle Scholar
  22. Das, M. P., Howard, E. D., Weiner, H. L., Sobel, R. A., Kuchroo, V. K., and Sean Riminton, D. (1998). Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. Journal of Immunology 161, 3299–306.Google Scholar
  23. De Laurenzi, V., and Melino, G. (2000). Evolution of functions within the p53/p63/p73 family. Annals of the New York Academy of Sciences 926, 90–100.PubMedGoogle Scholar
  24. Deng, Y., Lin, Y., and Wu, X. (2002). TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 16, 33–45.PubMedGoogle Scholar
  25. Dittel, B. N., Merchant, R. M., and Janeway, C. A., Jr. (1999). Evidence for Fas-dependent and Fas-independent mechanisms in the pathogenesis of experimental autoimmune encephalomyelitis. Journal of Immunology 162, 6392–400.Google Scholar
  26. Dowling, P., Husar, W., Menonna, J., Donnenfeld, H., Cook, S., and Sidhu, M. (1997). Cell death and birth in multiple sclerosis brain. Journal of the Neurological Sciences 149, 1–11.PubMedGoogle Scholar
  27. Dowling, P., Shang, G., Raval, S., Menonna, J., Cook, S., and Husar, W. (1996). Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. Journal of Experimental Medicine 184, 1513–8.PubMedGoogle Scholar
  28. Eizenberg, O., Faber-Elman, A., Gottlieb, E., Oren, M., Rotter, V., and Schwartz, M. (1995). Direct involvement of p53 in programmed cell death of oligodendrocytes. EMBO Journal 14, 1136–44.PubMedGoogle Scholar
  29. Eizenberg, O., Faber-Elman, A., Gottlieb, E., Oren, M., Rotter, V., and Schwartz, M. (1996). p53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cells. Molecular and Cellular Biology 16, 5178–85.Google Scholar
  30. el-Deiry, W. S., Harper, J. W., O’Connor, P. M., Velculescu, V. E., Canman, C. E., Jackman, J., Pietenpol, J. A., Burrell, M., Hill, D. E., Wang, Y., and et al. (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54, 1169–74.PubMedGoogle Scholar
  31. el-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., and Vogelstein, B. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–25. Feldmann, M., Brennan, F. M., and Maini, R. N. (1996). Rheumatoid arthritis. Cell 85, 307–10. Ffrench-Constant, C. (1994). Pathogenesis of multiple sclerosis. Lancet 343, 271–5.Google Scholar
  32. Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997). Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the United States of America 94, 10895–900.PubMedGoogle Scholar
  33. Firestein, G. S., Yeo, M., and Zvaifler, N. J. (1995). Apoptosis in rheumatoid arthritis synovium. Journal of Clinical Investigation 96, 1631–8.PubMedGoogle Scholar
  34. French, L. E., and Tschopp, J. (1996). Constitutive Fas ligand expression in several non-lymphoid mouse tissues: implications for immune-protection and cell turnover. Behring Institute Mitteilungen 97, 156–60.PubMedGoogle Scholar
  35. Giordano, C., Stassi, G., De Maria, R., Todaro, M., Richiusa, R, Papoff, G., Ruberti, G., Bagnasco, M., Testi, R., and Galluzzo, A. (1997). Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science 275, 960–3.PubMedGoogle Scholar
  36. Goke, R., Goke, A., Goke, B., and Chen, Y. (2000). Regulation of TRAIL-induced apoptosis by transcription factors. Cellular Immunology 201, 77–82.PubMedGoogle Scholar
  37. Goke, R., Goke, A., Goke, B., El-Deiry, W. S., and Chen, Y. (2001). Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced apoptosis by induction of p2lwafl/cipl. Digestion 64, 75–80.PubMedGoogle Scholar
  38. Guan, B., Yue, P., Clayman, G. L., and Sun, S. Y. (2001). Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene. Journal of Cellular Physiology 188, 98–105.PubMedGoogle Scholar
  39. Hermeking, H., Lengauer, C., Polyak, K., He, T. C., Zhang, L., Thiagalingam, S., Kinzler, K. W., and Vogelstein, B. (1997). 14–3–3 sigma is a p53–regulated inhibitor of G2/M progression. Mol Cell 1, 3 – 11.Google Scholar
  40. Hilliard, B., Wilmen, A., Seidel, C., Liu, T. S., Goke, R., and Chen, Y. (2001). Roles of TNF-related apoptosis-inducing ligand in experimental autoimmune encephalomyelitis. Journal of Immunology 166, 1314–9.Google Scholar
  41. Hu, W. H., Johnson, H., and Shu, H. B. (1999). Tumor necrosis factor-related apoptosis-inducing ligand receptors signal NF-kappaB and JNK activation and apoptosis through distinct pathways.Google Scholar
  42. J Biol Chem 274,30603–10. Irwin, M. S., and Kaelin, W. G. (2001). p53 family update: p73 and p63 develop their own identities. Cell Growth and Differentiation 12,337–49.Google Scholar
  43. Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., and Weinberg, R. A. (1994). Tumor spectrum analysis in p53-mutant mice. Current Biology 4, 1–7.PubMedGoogle Scholar
  44. Jeremias, I., Herr, I., Boehler, T., and Debatin, K. M. (1998). TRAIL/Apo-2-ligand-induced apoptosis in human T cells. European Journal of Immunology 28, 143–52.PubMedGoogle Scholar
  45. Jo, M., Kim, T. H., Seol, D. W., Esplen, J. E., Dorko, K., Billiar, T. R., and Strom, S. C. (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6, 564–7. Kaelin, W. G., Jr. (1999). The p53 gene family. Oncogene 18, 7701–5.Google Scholar
  46. Kang, S. M., Schneider, D. B., Lin, Z., Hanahan, D., Dichek, D. A., Stock, P. G., and Baekkeskov, S. (1997). Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nature Medicine 3, 738–43.PubMedGoogle Scholar
  47. Kassiotis, G., Kollias, G., and Calida, D. M. (2001). Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. Journal of Experimental Medicine 193, 427–34.PubMedGoogle Scholar
  48. Komer, H., Riminton, D. S., Strickland, D. H., Lemckert, F. A., Pollard, J. D., and Sedgwick, J. D. (1997). Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting. Journal of Experimental Medicine 186, 1585–90.Google Scholar
  49. Kuchroo, V. K., Das, M. P., Brown, J. A., Ranger, A. M., Zamvil, S. S., Sobel, R. A., Weiner, H. L., Nabavi, N., and Glimcher, L. H. (1995). B7–1 and B7–2 costimulatory molecules differentially activate the TH1/TH2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–18.PubMedGoogle Scholar
  50. Kumar-Sinha, C., Varambally, S., Sreekumar, A., and Chinnaiyan, A. M. (2002). Molecular cross-talk between the TRAIL and interferon signaling pathways. J Biol Chem 277, 575–85.PubMedGoogle Scholar
  51. Ladiwala, U., Li, H., Antel, J. P., and Nalbantoglu, J. (1999). p53 induction by tumor necrosis factor-alpha and involvement of p53 in cell death of human oligodendrocytes. Journal of Neurochemistry 73, 605–11.Google Scholar
  52. Levrero, M., De Laurenzi, V., Costanzo, A., Gong, J., Wang, J. Y., and Melino, G. (2000). The p53/p63/p73 family of transcription factors: overlapping and distinct functions. Journal of Cell Science 113, 1661–70.PubMedGoogle Scholar
  53. Lin, Y., Devin, A., Cook, A., Keane, M. M., Kelliher, M., Lipkowitz, S., and Liu, Z. G. (2000). The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol 20, 6638–45.PubMedGoogle Scholar
  54. Liu, T. S., Hilliard, B., Samoilova, E. B., and Chen, Y. (2000). Differential roles of Fas ligand in spontaneous and actively induced autoimmune encephalomyelitis. Clinical Immunology 95, 203–11.PubMedGoogle Scholar
  55. Lynch, D. H., Campbell, K. A., Miller, R. E., Badley, A. D., and Paya, C. V. (1996). FasL/Fas and TNF/TNFR interactions in the regulation of immune responses and disease. Behring Inst Mitt, 175–84.Google Scholar
  56. Magnusson, C., and Vaux, D. L. (1999). Signalling by CD95 and TNF receptors: not only life and death. Immunol Cell Biol 77, 41–6.PubMedGoogle Scholar
  57. Maim, R. N., Elliott, M. J., Brennan, F. M., Williams, R. O., Chu, C. Q., Paleolog, E., Charles, P. J., Taylor, P. C., and Feldmann, M. (1995). Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease. Immunological Reviews 144, 195–223.Google Scholar
  58. Malinin, N. L., Boldin, M. P., Kovalenko, A. V., and Wallach, D. (1997). MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 385, 540–4.PubMedGoogle Scholar
  59. Mariani, S. M., and Krammer, P. H. (1998). Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells. European Journal of Immunology 28, 1492–8.PubMedGoogle Scholar
  60. Martin-Villalba, A., Herr, I., Jeremias, I., Hahne, M., Brandt, R., Vogel, J., Schenkel, J., Herdegen, T., and Debatin, K. M. (1999). CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. Journal of Neuroscience 19, 3809–17.PubMedGoogle Scholar
  61. Meng, R. D., McDonald, E. R., 3rd, Sheikh, M. S., Fornace, A. J., Jr., and El-Deiry, W. S. (2000). The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Molecular Therapy: the Journal of the American Society of Gene Therapy 1, 130–44.Google Scholar
  62. Miller, S. D., and Karpus, W. J. (1994). The immunopathogenesis and regulation of T-cell-mediated demyelinating diseases. Immunology Today 15, 356–61.PubMedGoogle Scholar
  63. Miller, S. D., McRae, B. L., Vanderlugt, C. L., Nikcevich, K. M., Pope, J. G., Pope, L., and Karpus, W. J. (1995). Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunological Reviews 144, 225–44.PubMedGoogle Scholar
  64. Miller-Blair, D. J., and Robbins, D. L. (1993). Rheumatoid arthritis: new science, new treatment. Geriatrics 48, 28–38.PubMedGoogle Scholar
  65. Mills, A. A., Zheng, B., Wang, X. J., Vogel, H., Roop, D. R., and Bradley, A. (1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–13.Google Scholar
  66. Miyashita, T., and Reed, J. C. (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–9.PubMedGoogle Scholar
  67. Moon, C., Kim, S., Wie, M., Kim, H., Cheong, J., Park, J., Jee, Y., Tanuma, N., Matsumoto, Y., and Shin, T. (2000). Increased expression of p53 and Bax in the spinal cords of rats with experimental autoimmune encephalomyelitis. Neuroscience Letters 289, 41–4.PubMedGoogle Scholar
  68. Morrison, R. S., and Kinoshita, Y. (2000). The role of p53 in neuronal cell death. Cell Death and Differentiation 7, 868–79.PubMedGoogle Scholar
  69. Mountz, J. D., Edwards, C. K., 3rd, Cheng, J., Yang, P., Wang, Z., Liu, C., Su, X., Bluethmann, H., and Zhou, T. (1996). Autoimmunity due to defective Nur77, Fas, and TNF-RI apoptosis. Adv Exp Med Biol 406, 241–62.PubMedGoogle Scholar
  70. Muller, M., Wilder, S., Bannasch, D., Israeli, D., Lehlbach, K., Li-Weber, M., Friedman, S. L., Galle, P. R., Stremmel, W., Oren, M., and Krammer, P. H. (1998). p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. Journal of Experimental Medicine 188, 2033–45.Google Scholar
  71. Myers, L. K. (1993). Collagen-induced arthrits. In Current protocols in immunology, J. E. Coligan, ed. ( New York: Sarah Greene), pp. 15. 5. 1–24.Google Scholar
  72. Nagata, S., and Golstein, P. (1995). The Fas death factor. Science 267, 1449–56.PubMedGoogle Scholar
  73. Nagata, S., and Suda, T. (1995). Fas and Fas ligand: 1pr and gld mutations. Immunology Today 16, 39–43.Google Scholar
  74. Ozawa, K., Suchanek, G., Breitschopf, H., Bruck, W., Budka, H., Jellinger, K., and Lassmann, H. (1994). Patterns of oligodendroglia pathology in multiple sclerosis. Brain 117, 1311–22.Google Scholar
  75. Pan, G., Ni, J., Wei, Y. F., Yu, G., Gentz, R., and Dixit, V. M. (1997). An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277, 815–8.PubMedGoogle Scholar
  76. Pan, G., Ni, J., Yu, G., Wei, Y. F., and Dixit, V. M. (1998). TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Letters 424, 41–5.PubMedGoogle Scholar
  77. Pan, G., O’Rourke, K., Chinnaiyan, A. M., Gentz, R., Ebner, R., Ni, J., and Dixit, V. M. (1997). The receptor for the cytotoxic ligand TRAIL. Science 276, 111–3.PubMedGoogle Scholar
  78. Panayi, G. S. (1993). The pathogenesis of rheumatoid arthritis: from molecules to the whole patient. British Journal of Rheumatology 32, 533–6.PubMedGoogle Scholar
  79. Pender, M. E, McCombe, P. A., Yoong, G., and Nguyen, K. B. (1992). Apoptosis of alpha beta T lymphocytes in the nervous system in experimental autoimmune encephalomyelitis: its possible implications for recovery and acquired tolerance. Journal of Autoimmunity 5, 401–10.PubMedGoogle Scholar
  80. Pesch, J., Brehm, U., Staib, C., and Grummt, F. (1996). Repression of interleukin-2 and interleukin-4 promoters by tumor suppressor protein p53. J Interferon Cytokine Res 16, 595–600.PubMedGoogle Scholar
  81. Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., and Vogelstein, B. (1997). A model for p53-induced apoptosis. Nature 389, 300–5.PubMedGoogle Scholar
  82. Ruddle, N. H. (1992). Tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta). Curr Opin Immunol 4, 327–32.PubMedGoogle Scholar
  83. Saas, P., Walker, P. R., Hahne, M., Quiquerez, A. L., Schnuriger, V., Perrin, G., French, L., Van Meir, E. G., de Tribolet, N., Tschopp, J., and Dietrich, P. Y. (1997). Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? Journal of Clinical Investigation 99, 1173–8.PubMedGoogle Scholar
  84. Sabelko, K. A., Kelly, K. A., Mnahm, M. H., Cross, A. H., and Russell, J. H. (1997). Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system. Journal of Immunology 159, 3096–3099.Google Scholar
  85. Sabelko-Downes, K. A., Cross, A. H., and Russell, J. H. (1999). Dual Role for Fas Ligand in the Initiation of and Recovery from Experimental Allergic Encephalomyelitis. J. Exp. Med. 189, 1195–1205.PubMedGoogle Scholar
  86. Sakhi, S., Bruce, A., Sun, N., Tocco, G., Baudry, M., and Schreiber, S. S. (1994). p53 induction is associated with neuronal damage in the central nervous system. Proceedings of the National Academy of Sciences of the United States of America 91, 7525–9.Google Scholar
  87. Salmon, M., and Gaston, J. S. (1995). The role of T-lymphocytes in rheumatoid arthritis. British Medical Bulletin 51, 332–45.PubMedGoogle Scholar
  88. Santhanam, U., Ray, A., and Sehgal, P. B. (1991). Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A 88, 7605–9.PubMedGoogle Scholar
  89. Sartor, R. B., Rath, H. C., Lichtman, S. N., and van Tol, E. A. (1996). Animal models of intestinal and joint inflammation. Baillieres Clinical Rheumatology 10, 55–76.Google Scholar
  90. Schmied, M., Breitschopf, H., Gold, R., Zischler, H., Rothe, G., Wekerle, H., and Lassmann, H. (1993). Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. American Journal of Pathology 143, 446–52.PubMedGoogle Scholar
  91. Schneider, E, Bodmer, J. L., Thome, M., Hofmann, K., Holler, N., and Tschopp, J. (1997). Characterization of two receptors for TRAIL. FEBS Letters 416, 329–34.PubMedGoogle Scholar
  92. Schneider, P., Thome, M., Bums, K., Bodmer, J. L., Hofmann, K., Kataoka, T., Holler, N., and Tschopp, J. (1997). TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7, 831–6.PubMedGoogle Scholar
  93. Schumacher, H. R., Jr., Bautista, B. B., Krauser, R. E., Mathur, A. K., and Gall, E. P. (1994). Histological appearance of the synovium in early rheumatoid arthritis. Seminars in Arthritis & Rheumatism 23, 3–10.Google Scholar
  94. Screaton, G. R., Mongkolsapaya, J., Xu, X. N., Cowper, A. E., McMichael, A. J., and Bell, J. I. (1997). TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Current Biology 7, 693–6.PubMedGoogle Scholar
  95. Sewell, K. L., and Trentham, D. E. (1993). Pathogenesis of rheumatoid arthritis. Lancet 341, 283–6.PubMedGoogle Scholar
  96. Sheikh, M. S., Burns, T. F., Huang, Y., Wu, G. S., Amundson, S., Brooks, K. S., Fornace, A. J., Jr., and el-Deiry, W. S. (1998). p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Research 58, 1593–8.Google Scholar
  97. Sheikh, M. S., Huang, Y., Fernandez-Salas, E. A., El-Deiry, W. S., Friess, H., Amundson, S., Yin, J., Meltzer, S. J., Holbrook, N. J., and Fornace, A. J., Jr. (1999). The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 18, 4153–9.PubMedGoogle Scholar
  98. Sheridan, J. P., Marsters, S. A., Pitti, R. M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C. L., Baker, K., Wood, W. I., Goddard, A. D., Godowski, P., and Ashkenazi, A. (1997). Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818–21.PubMedGoogle Scholar
  99. Simon, A. K., Williams, O., Mongkolsapaya, J., Jin, B., Xu, X. N., Walczak, H., and Screaton, G. R. (2001). Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes. Proc Natl Acad Sci U S A 98, 5158–63.PubMedGoogle Scholar
  100. Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middelton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., and Straus, S. E. (1997). Clincial, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89, 1341–8.PubMedGoogle Scholar
  101. Song, K., Chen, Y., Goke, R., Wilmen, A., Seidel, C., Goke, A., Hilliard, B., and Chen, Y. (2000). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 191, 1095–104.PubMedGoogle Scholar
  102. Sprick, M. R., Weigand, M. A., Rieser, E., Rauch, C. T., Juo, P., Blenis, J., Krammer, P. H., and Walczak, H. (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12, 599–609.PubMedGoogle Scholar
  103. Stuart, P. M., Griffith, T. S., Usui, N., Pepose, J., Yu, X., and Ferguson, T. A. (1997). CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. Journal of Clinical Investigation 99, 396–402.PubMedGoogle Scholar
  104. Suvannavejh, G. C., Dal Canto, M. C., Matis, L. A., and Miller, S. D. (2000). Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis. Journal of Clinical Investigation 105, 223–31.PubMedGoogle Scholar
  105. Tanaka, H., Ota, K., Ikusaka, M., Ejima, M., and Maruyama, S. (1995). Expression of Fas-antigen on T cells in multiple sclerosis. Rinsho Shinkeigaku-Clinical Neurology 35, 299–301.PubMedGoogle Scholar
  106. Utrera, R., Collavin, L., Lazarevic, D., Delia, D., and Schneider, C. (1998). A novel p53-inducible gene coding for a microtubule-localized protein with G2-phase-specific expression. Embo J 17, 5015–25.PubMedGoogle Scholar
  107. Walczak, H., Degli-Esposti, M. A., Johnson, R. S., Smolak, P. J., Waugh, J. Y., Boiani, N., Timour, M. S., Gerhart, M. J., Schooley, K. A., Smith, C. A., Goodwin, R. G., and Rauch, C. T. (1997). TRAIL-R2: a novel apoptosismediating receptor for TRAIL. EMBO Journal 16, 5386–97.Google Scholar
  108. Walczak, H., Miller, R. E., Ariail, K., Gliniak, B., Griffith, T. S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., Smith, C., Smolak, P., Goodwin, R. G., Rauch, C. T., Schuh, J. C., and Lynch, D. H. (1999). Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Medicine 5, 157–63.PubMedGoogle Scholar
  109. Waldner, H., Sobel, R. A., Howard, E., and Kuchroo, V. K. (1997). Fas-and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. Journal of Immunology 159, 3100–03.Google Scholar
  110. Wallach, D., Boldin, M., Goncharov, T., Goltsev, Y., Mett, I., Malinin, N., Adar, R., Kovalenko, A., and Varfolomeev, E. (1996). Exploring cell death mechanisms by analyzing signaling cascades of the TNF/NGF receptor family. Behring Inst Mitt, 144–55.Google Scholar
  111. Ware, C. F., VanArsdale, S., and VanArsdale, T. L. (1996). Apoptosis mediated by the TNF-related cytokine and receptor families. J Cell Biochem 60, 47–55.PubMedGoogle Scholar
  112. Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C. R, Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–82.Google Scholar
  113. Wu, G. S., Burns, T. F., McDonald, E. R. r., Jiang, W., Meng, R., Krantz, I. D., Kao, G., Gan, D. D., Zhou, J. Y., Muschel, R., Hamilton, S. R., Spinner, N. B., Markowitz, S., Wu, G., and el-Deiry, W. S. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genetics 17, 141–3.PubMedGoogle Scholar
  114. Wu, G. S., Burns, T. F., Zhan, Y., Alnemri, E. S., and El-Deiry, W. S. (1999). Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) death receptor. Cancer Research 59, 2770–5.Google Scholar
  115. Xerri, L., Devilard, E., Hassoun, J., Mawas, C., and Birg, F. (1997). Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues. Molecular Pathology 50, 87–91.PubMedGoogle Scholar
  116. Yamanishi, Y., Boyle, D. L., Pinkoski, M. J., Mahboubi, A., Lin, T., Han, Z., Zvaifler, N. J., Green, D. R., and Firestein, G. S. (2002). Regulation of Joint Destruction and Inflammation by p53 in Collagen-Induced Arthritis. Am J Pathol 160, 123–30.PubMedGoogle Scholar
  117. Yamanishi, Y., Boyle, D. L., Rosengren, S., Green, D. R., Zvaifler, N. J., and Firestein, G. S. (2002). Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the United States of America 99, 10025–30.PubMedGoogle Scholar
  118. Yang, A., Walker, N., Bronson, R., Kaghad, M., Oosterwegel, M., Bonnin, J., Vagner, C., Bonnet, H., Dikkes, P., Sharpe, A., McKeon, F., and Caput, D. (2000). p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99–103.Google Scholar
  119. Yao, Q., Wang, S., Glorioso, J. C., Evans, C. H., Robbins, P. D., Ghivizzani, S. C., and Oligino, T. J. (2001). Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Molecular Therapy 3, 901–10.PubMedGoogle Scholar
  120. Zamvil, S. S., and Steinman, L. (1990). The T lymphocyte in experimental allergic encephalomyelitis. Ann. Rev. Immunol. 8, 579–621.Google Scholar
  121. Zhan, Q., Bae, I., Kastan, M. B., and Fornace, A. J., Jr. (1994). The p53-dependent gamma-ray response of GADD45. Cancer Res 54, 2755–60.PubMedGoogle Scholar
  122. Zhang, X. D., Zhang, X. Y., Gray, C. R, Nguyen, T., and Hersey, P. (2001). Tumor necrosis factor-related apoptosisinducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Cancer Res 61, 7339–48.PubMedGoogle Scholar

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© Springer Science+Business Media New York 2003

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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