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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2009

Open Access 01-02-2009 | Research article

Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium

Authors: Anak ASSK Dharmapatni, Malcolm D Smith, David M Findlay, Christopher A Holding, Andreas Evdokiou, Michael J Ahern, Helen Weedon, Paul Chen, Gavin Screaton, Xiao N Xu, David R Haynes

Published in: Arthritis Research & Therapy | Issue 1/2009

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Abstract

Introduction

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumour necrosis factor (TNF) family member capable of inducing apoptosis in many cell types.

Methods

Using immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and real-time PCR we investigated the expression of TRAIL, TRAIL receptors and several key molecules of the intracellular apoptotic pathway in human synovial tissues from various types of arthritis and normal controls. Synovial tissues from patients with active rheumatoid arthritis (RA), inactive RA, osteoarthritis (OA) or spondyloarthritis (SpA) and normal individuals were studied.

Results

Significantly higher levels of TRAIL, TRAIL R1, TRAIL R2 and TRAIL R4 were observed in synovial tissues from patients with active RA compared with normal controls (p < 0.05). TRAIL, TRAIL R1 and TRAIL R4 were expressed by many of the cells expressing CD68 (macrophages). Lower levels of TUNEL but higher levels of cleaved caspase-3 staining were detected in tissue from active RA compared with inactive RA patients (p < 0.05). Higher levels of survivin and x-linked inhibitor of apoptosis protein (xIAP) were expressed in active RA synovial tissues compared with inactive RA observed at both the protein and mRNA levels.

Conclusions

This study indicates that the induction of apoptosis in active RA synovial tissues is inhibited despite stimulation of the intracellular pathway(s) that lead to apoptosis. This inhibition of apoptosis was observed downstream of caspase-3 and may involve the caspase-3 inhibitors, survivin and xIAP.
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Literature
1.
Hsu HC, Wu Y, Mountz JD: Tumor necrosis factor ligand-receptor superfamily and arthritis. Curr Dir Autoimmun. 2006, 9: 37-54.PubMed
2.
Vaishnaw AK, McNally JD, Elkon KB: Apoptosis in the rheumatic diseases. Arthritis Rheum. 1997, 40: 1917-1927. 10.1002/art.1780401102.CrossRefPubMed
3.
Fujisawa K, Asahara H, Okamoto K, Aono H, Hasunuma T, Kobata T, Iwakura Y, Yonehara S, Sumida T, Nishioka K: Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest. 1996, 98: 271-278. 10.1172/JCI118789.PubMedCentralCrossRefPubMed
4.
Okamoto K, Asahara H, Kobayashi T, Matsuno H, Hasunuma T, Kobata T, Sumida T, Nishioka K: Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer. Gene Ther. 1998, 5: 331-338. 10.1038/sj.gt.3300597.CrossRefPubMed
5.
Nesterov A, Ivashchenko Y, Kraft AS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in normal prostate epithelial cells. Oncogene. 2002, 21: 1135-1140. 10.1038/sj.onc.1205151.CrossRefPubMed
6.
Pettersen I, Figenschau Y, Olsen E, Bakkelund W, Smedsrod B, Sveinbjornsson B: Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in human articular chondrocytes in vitro. Biochem Biophys Res Commun. 2002, 296: 671-676. 10.1016/S0006-291X(02)00916-6.CrossRefPubMed
7.
Di Pietro R, Mariggio MA, Guarnieri S, Sancilio S, Giardinelli A, Di Silvestre S, Consoli A, Zauli G, Pandolfi A: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) regulates endothelial nitric oxide synthase (eNOS) activity and its localization within the human vein endothelial cells (HUVEC) in culture. J Cell Biochem. 2006, 97: 782-794. 10.1002/jcb.20686.CrossRefPubMed
8.
Diehl GE, Yue HH, Hsieh K, Kuang AA, Ho M, Morici LA, Lenz LL, Cado D, Riley LW, Winoto A: TRAIL-R as a negative regulator of innate immune cell responses. Immunity. 2004, 21: 877-889. 10.1016/j.immuni.2004.11.008.CrossRefPubMed
9.
Kimberley FC, Screaton GR: Following a TRAIL: update on a ligand and its five receptors. Cell Res. 2004, 14: 359-372. 10.1038/sj.cr.7290236.CrossRefPubMed
10.
Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR: Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998, 273: 14363-14367. 10.1074/jbc.273.23.14363.CrossRefPubMed
11.
Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ: Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol. 1998, 161: 2833-2840.PubMed
12.
Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997, 388: 300-304. 10.1038/40901.CrossRefPubMed
13.
Evdokiou A, Bouralexis S, Atkins GJ, Chai F, Hay S, Clayer M, Findlay DM: Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. Int J Cancer. 2002, 99: 491-504. 10.1002/ijc.10376.CrossRefPubMed
14.
Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG: The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity. 1997, 7: 813-820. 10.1016/S1074-7613(00)80399-4.CrossRefPubMed
15.
Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P: Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res. 1999, 59: 2747-2753.PubMed
16.
Koornstra JJ, Kleibeuker JH, van Geelen CM, Rijcken FE, Hollema H, de Vries EG, de Jong S: Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas. J Pathol. 2003, 200: 327-335. 10.1002/path.1364.CrossRefPubMed
17.
Song K, Chen Y, Goke R, Wilmen A, Seidel C, Goke A, Hilliard B, Chen Y: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med. 2000, 191: 1095-1104. 10.1084/jem.191.7.1095.PubMedCentralCrossRefPubMed
18.
Ichikawa K, Liu W, Fleck M, Zhang H, Zhao L, Ohtsuka T, Wang Z, Liu D, Mountz JD, Ohtsuki M, Koopman WJ, Kimberly R, Zhou T: TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. J Immunol. 2003, 171: 1061-1069.CrossRefPubMed
19.
Miranda-Carus ME, Balsa A, Benito-Miguel M, De Ayala CP, Martin-Mola E: Rheumatoid arthritis synovial fluid fibroblasts express TRAIL-R2 (DR5) that is functionally active. Arthritis Rheum. 2004, 50: 2786-2793. 10.1002/art.20501.CrossRefPubMed
20.
Miyashita T, Kawakami A, Nakashima T, Yamasaki S, Tamai M, Tanaka F, Kamachi M, Ida H, Migita K, Origuchi T, Nakao K, Eguchi K: Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells. Clin Exp Immunol. 2004, 137: 430-436. 10.1111/j.1365-2249.2004.02534.x.PubMedCentralCrossRefPubMed
21.
Morel J, Audo R, Hahne M, Combe B: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem. 2005, 280: 15709-15718. 10.1074/jbc.M414469200.CrossRefPubMed
22.
Liu Z, Xu X, Hsu HC, Tousson A, Yang PA, Wu Q, Liu C, Yu S, Zhang HG, Mountz JD: CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. J Clin Invest. 2003, 112: 1332-1341.PubMedCentralCrossRefPubMed
23.
Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin T, Yu VL, Miller DK: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995, 376: 37-43. 10.1038/376037a0.CrossRefPubMed
24.
Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ: Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28- T cells from rheumatoid arthritis patients. J Immunol. 1998, 161: 1018-1025.PubMed
25.
Bokarewa M, Lindblad S, Bokarew D, Tarkowski A: Balance between survivin, a key member of the apoptosis inhibitor family, and its specific antibodies determines erosivity in rheumatoid arthritis. Arthritis Res Ther. 2005, 7: R349-358. 10.1186/ar1498.PubMedCentralCrossRefPubMed
26.
Miyashita T, Kawakami A, Tamai M, Izumi Y, Mingguo H, Tanaka F, Abiru S, Nakashima K, Iwanaga N, Aratake K, Kamachi M, Arima K, Ida H, Migita K, Origuchi T, Tagashira S, Nishikaku F, Eguchi K: Akt is an endogenous inhibitor toward tumor necrosis factor-related apoptosis inducing ligand-mediated apoptosis in rheumatoid synovial cells. Biochem Biophys Res Commun. 2003, 312: 397-404. 10.1016/j.bbrc.2003.10.141.CrossRefPubMed
27.
Perlman H, Nguyen N, Liu H, Eslick J, Esser S, Walsh K, Moore TL, Pope RM: Rheumatoid arthritis synovial fluid macrophages express decreased tumor necrosis factor-related apoptosis-inducing ligand R2 and increased decoy receptor tumor necrosis factor-related apoptosis-inducing ligand R3. Arthritis Rheum. 2003, 48: 3096-3101. 10.1002/art.11302.CrossRefPubMed
28.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, LA H, Kaplan SR, Liang MH, Luthra HS, Medsger TA, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002/art.1780310302.CrossRefPubMed
29.
Altman R, Bloch DA, Bole G, Borenstain D, Brant K, Christy W, Cooke TD, Greenwald R, Hochberg M, Howell D, Kaplan D, Koopman W, Longley S, Mankin H, McShane DJ, Medsger T, Meenan R, Mikkelsen W, Moskowitz R, Murphy W, Rothschild B, Segal M, Sokoloff L, Wolfe F: Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum. 1986, 29: 1039-1049. 10.1002/art.1780290816.CrossRefPubMed
30.
Dougados M, Linden van der S, Juhlin R, Huitfeldt B, Amor B, Calin A, Cats A, Dijkmans B, Olivieri I, Pasero G, et al: The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991, 34: 1218-1227. 10.1002/art.1780341003.CrossRefPubMed
31.
Ch'en PF, Xu XG, Liu XS, Liu Y, Song CJ, Screaton GR, Jin BQ, Xu XN: Characterisation of monoclonal antibodies to the TNF and TNF receptor families. Cell Immunol. 2005, 236: 78-85. 10.1016/j.cellimm.2005.08.010.CrossRefPubMed
32.
Haynes DR, Barg E, Crotti TN, Holding C, Weedon H, Atkins GJ, Zannetino A, Ahern MJ, Coleman M, Roberts-Thomson PJ, Kraan M, Tak PP, Smith MD: Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathies and osteoarthritis and normal controls. Rheumatology (Oxford). 2003, 42: 123-134. 10.1093/rheumatology/keg047.CrossRef
33.
Smith MD, O'Donnell J, Highton J, Palmer DG, Rozenbilds M, Roberts-Thomson PJ: Immunohistochemical analysis of synovial membranes from inflammatory and non-inflammatory arthritides: scarcity of CD5 positive B cells and IL2 receptor bearing T cells. Pathology. 1992, 24: 19-26. 10.3109/00313029209063615.CrossRefPubMed
34.
Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, Tak PP, Haynes DR: Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis. 2002, 61: 1047-1054. 10.1136/ard.61.12.1047.PubMedCentralCrossRefPubMed
35.
Tak PP, Lubbe van der PA, Cauli A, Daha MR, Smeets TJ, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC: Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis. Arthritis Rheum. 1995, 38: 1457-1465. 10.1002/art.1780381012.CrossRefPubMed
36.
Krepela E, Prochazka J, Fiala P, Zatloukal P, Selinger P: Expression of apoptosome pathway-related transcripts in non-small cell lung cancer. J Cancer Res Clin Oncol. 2006, 132: 57-68. 10.1007/s00432-005-0048-6.CrossRefPubMed
37.
Schultz IJ, Kiemeney LA, Witjes JA, Schalken JA, Willems JL, Swinkels DW, de Kok JB: Survivin mRNA expression is elevated in malignant urothelial cell carcinomas and predicts time to recurrence. Anticancer Res. 2003, 23: 3327-3331.PubMed
38.
Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine NR: Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer. 2007, 120: 2344-2352. 10.1002/ijc.22554.CrossRefPubMed
39.
Franssen ME, Zeeuwen PL, Vierwinden G, Kerkhof van de PC, Schalkwijk J, van Erp PE: Phenotypical and functional differences in germinative subpopulations derived from normal and psoriatic epidermis. J Invest Dermatol. 2005, 124: 373-383. 10.1111/j.0022-202X.2004.23612.x.CrossRefPubMed
40.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
41.
Zhang L, Fang B: Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 2005, 12: 228-237. 10.1038/sj.cgt.7700792.CrossRefPubMed
42.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997, 277: 818-821. 10.1126/science.277.5327.818.CrossRefPubMed
43.
Kim K, Fisher MJ, Xu SQ, el-Deiry WS: Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res. 2000, 6: 335-346.PubMed
44.
Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A: A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 1997, 7: 1003-1006. 10.1016/S0960-9822(06)00422-2.CrossRefPubMed
45.
Jungel A, Baresova V, Ospelt C, Simmen BR, Michel BA, Gay RE, Gay S, Seemayer CA, Neidhart M: Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis. 2006, 65: 910-912. 10.1136/ard.2005.044065.PubMedCentralCrossRefPubMed
46.
Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P: Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. J Immunol. 2000, 164: 3961-3970.CrossRefPubMed
47.
Smith MD, Kraan MC, Slavotinek J, Au V, Weedon H, Parker A, Coleman M, Roberts-Thomson PJ, Ahern MJ: Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies. Rheumatology (Oxford). 2001, 40: 367-374. 10.1093/rheumatology/40.4.367.CrossRef
48.
Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, Salvesen GS, Reed JC, Altieri DC: An IAP-IAP complex inhibits apoptosis. J Biol Chem. 2004, 279: 34087-34090. 10.1074/jbc.C400236200.CrossRefPubMed
49.
Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y: Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000, 408: 1008-1012. 10.1038/35050012.CrossRefPubMed
50.
Catrina AI, Ulfgren AK, Lindblad S, Grondal L, Klareskog L: Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann Rheum Dis. 2002, 61: 934-936. 10.1136/ard.61.10.934.PubMedCentralCrossRefPubMed
Metadata
Title
Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium
Authors
Anak ASSK Dharmapatni
Malcolm D Smith
David M Findlay
Christopher A Holding
Andreas Evdokiou
Michael J Ahern
Helen Weedon
Paul Chen
Gavin Screaton
Xiao N Xu
David R Haynes
Publication date
01-02-2009
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2009
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2603

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