TL1A-induced NF-κB Activation and c-IAP2 Production Prevent DR3-mediated Apoptosis in TF-1 Cells

Abstract

We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3 (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-κB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-κB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-κB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-κB-dependent anti-apoptotic protein, and that the NF-κB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells. We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3 (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-κB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-κB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-κB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-κB-dependent anti-apoptotic protein, and that the NF-κB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells. Death receptors of the tumor necrosis factor receptor (TNFR) 1The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; FADD, Fas-associated death domain; TRADD, TNFR-associated death domain; TRAF2, TNFR-associated factor-2; RIP, receptor interactive protein; c-IAP, cellular inhibitor of apoptosis protein; DR, death receptor(s); DR3Δ DD, DR3 death-domain deleted; c-FLIP, FLICE inhibitory protein; XIAP, X chromosome-linked IAP; Bcl-2, B-cell lymphoma 2; mAb, monoclonal antibody; CHX, cycloheximide; FBS, fetal bovine serum; SEAP, secreted alkaline phosphatase; siRNA, small interfering RNA; SRE, serum response element.1The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; FADD, Fas-associated death domain; TRADD, TNFR-associated death domain; TRAF2, TNFR-associated factor-2; RIP, receptor interactive protein; c-IAP, cellular inhibitor of apoptosis protein; DR, death receptor(s); DR3Δ DD, DR3 death-domain deleted; c-FLIP, FLICE inhibitory protein; XIAP, X chromosome-linked IAP; Bcl-2, B-cell lymphoma 2; mAb, monoclonal antibody; CHX, cycloheximide; FBS, fetal bovine serum; SEAP, secreted alkaline phosphatase; siRNA, small interfering RNA; SRE, serum response element. superfamily induce programmed cell death or apoptosis that plays crucial roles in immune modulation, organ development, and tissue homeostasis (2Ware C.F. Santee S. Glass A.A. The Cytokine Handbook. 3rd Ed. Academic Press, Orlando, FL1998: 549-591Google Scholar, 3Chan F.K. Siegel R.M. Lenardo M.J. Immunity. 2000; 13: 419-422Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 4Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2984) Google Scholar, 5Ashkenazi A. Nat. Rev. Cancer. 2002; 2: 420-430Crossref PubMed Scopus (1099) Google Scholar). Although TRAIL-induced apoptosis through activation of DR4 or DR5 is important in eliminating cancer and virus-infected cells, FasL-mediated Fas activation leads to activation-induced T cell death and lymphocyte homeostasis. Identification of the signaling molecules and signal transduction pathways activated by the death receptors has greatly enhanced our understanding of this death receptor-dependent extrinsic apoptosis pathway as well as the physiological and pathological functions of the death receptors (Refs. 6Ashkenazi A. Dixit V.M. Curr. Opin. Cell Biol. 1999; 11: 255-260Crossref PubMed Scopus (1147) Google Scholar, 7Baud V. Karin M. Trends Cell Biol. 2001; 11: 372-377Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar, 8Gupta S. Curr. Mol. Med. 2001; 1: 317-324Crossref PubMed Scopus (56) Google Scholar and references within). Among them, TNFR1, Fas, DR4, and DR5 are the best studied. Binding of FasL or TRAIL to cell surface Fas or DR4 (or DR5), respectively, triggers the association of the intracellular adaptor protein Fas-associated death domain (FADD) to the death domain of the receptor and the activation of caspase-8 and/or caspase-10. These initiator caspases induce a cascade of caspase activation that leads to the activation of effector caspases, including caspase-3, -6, and -7, and ultimately cell death. On the other hand, signal transduction induced by TNF binding to TNFR1 first recruits intracellular TNFR-associated death domain (TRADD). As a platform adaptor, TRADD then recruits the adaptor protein FADD, TNFR-associated factor-2 (TRAF2), and receptor interactive protein (RIP) to stimulate apoptosis, mitogen-activated protein kinase (MAPK) activation, and NF-κB activation, respectively. Consistent with their ability to activate different signaling pathways, death receptors such as Fas, DR4, and DR5 preferentially induce apoptosis, TNFR1 cell or death the cellular the study of apoptosis, that NF-κB is a of a the or death of a cell plays a in inhibition of apoptosis by activation of A. D. Scopus Google Scholar, Karin M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, Trends Cell Biol. Full Text PDF PubMed Scopus Google Scholar, M. A. Nat. 2002; PubMed Scopus Google Scholar). Among the NF-κB members of the cellular inhibitor of apoptosis such as and c-IAP2, have to cell death by effector caspases N. R. J. 16: PubMed Scopus Google Scholar, N. Zhou S.M. J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, E. S. J. Biol. 2000; Full Text Full Text PDF PubMed Google Scholar, 2000; and/or of apoptosis S. X. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). DR3 is of the death receptors in the and its is to M. L. Gentz R. Ni J. Dixit V.M. PubMed Scopus Google Scholar, P. V. M. M. M. A. J. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, J. R. PubMed Scopus Google Scholar, R.M. A. Curr. Biol. Full Text Full Text PDF PubMed Google Scholar, J. M. P. J. J. Moore G. A. PubMed Scopus Google Scholar, Olsen R. S. A. PubMed Scopus Google Scholar). of DR3 in cell induced NF-κB activation and triggered apoptosis M. L. Gentz R. Ni J. Dixit V.M. PubMed Scopus Google Scholar, P. V. M. M. M. A. J. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, R.M. A. Curr. Biol. Full Text Full Text PDF PubMed Google Scholar). DR3 to to signal TRAF2, RIP, FADD, and caspase-8 through the association with TRADD M. L. Gentz R. Ni J. Dixit V.M. PubMed Scopus Google Scholar). to TNFR1, DR3-induced apoptosis is and in A. M. A. PubMed Scopus Google Scholar, M. V. N. J.S. D. V.M. D. P. D. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). However, these were in DR3 and/or the signaling molecules were The physiological signal activated by DR3 through its ligand have not studied. we have the and of TL1A, a of the TNF superfamily of and a ligand for DR3 (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). Interestingly, we found that of TL1A of the TF-1 human erythroleukemic or T cells, which express did not in apoptosis. cell death was induced in TF-1 cells TL1A was used with a protein cycloheximide (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). Furthermore, the physiological of DR3 in apoptosis was by DR3 in which of DR3 in to of T cells in the A. A. J. M.J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). To understand the molecular for this cell apoptosis by we the signal and signaling pathways activated by TL1A-DR3 interaction and studied the roles of these pathways in DR3 apoptosis in TF-1 cells. TF-1 cells are cells, and understanding the of TL1A and DR3 in the of these cells have physiological and Our study that in these cells, TL1A binding to DR3 the formation of a signaling complex containing TRADD, TRAF2, and RIP but detectable of FADD, or Although the NF-κB and pathways were activated by either TL1A or a DR3 agonistic monoclonal antibody we found that DR3-induced NF-κB activation a in cell fate in these cells, and is in through c-IAP2, a known and Cell for human DR3Δ DD, and as well as cell and DR3Δ DD, have (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). Death DR3 DD, was and cell human DR3Δ or DR3Δ were in cells with of were by of and by and and and a were in as E. D. Scholar). and TRADD, TRAF2, and were p38 and were and were and the and and were and were was The NF-κB pathway-specific inhibitor and were The inhibitor inhibitor and p38 inhibitor were and cell caspase were as (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). the cells were in in containing fetal bovine serum The cells were then with or with or cycloheximide for or in the presence or of different kinase for different caspase was in the a caspase that activation of -6, -7, and of was a with and The for have in (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). cells in were and in The cells were with and a was and in of inhibitor and for The cell was by for The cell were with of or and of protein for with The were then with containing and with in for and cell the the of NF-κB or were P.A. S. D. Zhang J. Ruben S. 1999; PubMed Scopus Google Scholar). The cells in were and in containing with different of or in the presence or of or The were and was a of and of cells in were in containing for The cells were then with of or for different the of of cells were and for in of The signaling molecules were to and with by and with was and for to of in TF-1 cells in were and in and factor The cells were with or for different or for 3 with or inhibitor or of cells were and with inhibitor and The were then of cell and by and c-IAP2 and to and of the human c-IAP2 and were of was TF-1 cells in of by a and The cells were then to with and for with or for The caspase was then as and of a study the signal transduction pathways and signaling molecules activated by we human DR3 E. D. Scholar). The were by for their ability to cells a death human DR3 DD, (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). to a TL1A protein (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google antibody to cells but not the cells. antibody did not cells, nor did cells the DR3Δ extracellular domain is to that of human DR3 Furthermore, we found that the binding of to cells, and TL1A with for binding to the cells not These that antibody the extracellular domain of human To antibody is an agonistic we of the that the human TL1A protein caspase activation and programmed cell death in TF-1 cells in the presence of (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google and antibody in the to the induced caspase activation and apoptosis in TF-1 cells in the presence of of CHX, an or the The for and in caspase were and respectively. effect apoptosis or caspase activation was seen TL1A or was used in the of and not These that is an agonistic antibody and nor alone apoptosis in TF-1 cells. However, apoptosis induced by or protein was study that caspase activation is with the of apoptosis in TF-1 cells. caspase activation was used as an of apoptosis in the of the TL1A-DR3 DR3 has to with TRAF2, RIP, FADD, and caspase-8 through TRADD in M. L. Gentz R. Ni J. Dixit V.M. PubMed Scopus Google DR3-induced signaling have not studied in cells that express To the physiological signal to DR3 TL1A we TF-1 cells with for and and the DR3 signaling complex was cell with antibody or of the protein by we found that TRADD, the platform adaptor, and signal and RIP were to DR3 and not DR3 signaling complex as as TL1A and for Interestingly, RIP to to the complex the of the FADD, or protein was in the of these molecules were in TF-1 cells with We that TF-1 cells a detectable of the c-IAP2 protein and Our that a physiological DR3 signaling complex in TF-1 cells TRADD, TRAF2, and RIP but not of FADD, or inhibitor or c-IAP2 synthesis. TF-1 cells were with in the presence or of NF-κB inhibitor or for 3 were and with of c-IAP2 production TF-1 cells to or apoptosis. The cells were with c-IAP2 or or with and for The cells were then either or with or for for c-IAP2 production by or caspase by caspase TL1A and NF-κB and JNK, and in TF-1 is known that TRADD, RIP, and are TNFR1 to that to the activation of NF-κB and MAPK, N-terminal as protein (Refs. 6Ashkenazi A. Dixit V.M. Curr. Opin. Cell Biol. 1999; 11: 255-260Crossref PubMed Scopus (1147) Google Scholar, 7Baud V. Karin M. Trends Cell Biol. 2001; 11: 372-377Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar, 8Gupta S. Curr. Mol. Med. 2001; 1: 317-324Crossref PubMed Scopus (56) Google Scholar and references within). To the DR3 signal transduction pathways in cells this receptor and to the effect of with DR3 we the of pathway-specific or in TF-1 cells. As a for the activation of in TF-1 cells, TNF, a known induced activation of pathways to TNF, activated not the NF-κB by but JNK, and signaling pathways were activated in a and of induced the were activated different activation of NF-κB and and were and was activated the or of the p38 to and and signal transduction induced by the DR3 agonistic antibody to induced by suggesting that TL1A through the DR3 receptor in TF-1 cells. To signal transduction to the and induce pathway-specific we the effect of and activation in TF-1 cells, in which the is either by the NF-κB or the serum response P.A. S. D. Zhang J. Ruben S. 1999; PubMed Scopus Google Scholar). is by ERK, JNK, and p38 P. PubMed Scopus Google Scholar, R. J. 16: PubMed Scopus Google the used to the effect of these cells were and induced production to in a activation was seen with or antibody were seen cells were of was with of either or These that TL1A-DR3 interaction activated the NF-κB and pathways and to pathway-specific of NF-κB and DR3-induced in TF-1 understand the of of the signaling pathways activated by DR3 in the and death of the we the effect of pathway-specific in the presence or of the DR3 agonistic antibody in TF-1 cells. and was to the of DR3-mediated apoptosis. The NF-κB pathway-specific inhibitor J. J. Biol. Full Text Full Text PDF PubMed Scopus Google was for this study NF-κB activation in cells, the effect As in and but not the antibody induced caspase activation to or was for caspase activation was in the presence of the other inhibitors, including inhibitor A. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google and inhibitor P.A. J. Biol. Full Text Full Text PDF PubMed Scopus Google inhibitor A. S. S. A. 2001; PubMed Scopus Google and p38 inhibitor A. J. R. P. PubMed Scopus Google alone or in combination, with cell and was seen for the the caspase of cells increased and the effect of of the and the with or a of and caspase activation, other caspase activation of Interestingly, we that the presence of the significantly the effect of to the TF-1 cells of with in were seen protein was used of not These that NF-κB is the pathway activated by DR3 that cells apoptosis. of c-IAP2 by through NF-κB understand the molecular mechanism by which NF-κB cells DR3-induced apoptosis, we NF-κB that have to a in apoptosis in or TF-1 cells M. A. Nat. 2002; PubMed Scopus Google Scholar). Among the anti-apoptotic including c-IAP2, inhibitory lymphoma and TRAF2, we that c-IAP2, which was in TF-1 cells, was significantly induced by TL1A or and not c-IAP2 was as as TL1A and to the We the of of death a in the of apoptosis Liu 1999; PubMed Scopus Google Scholar, J. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google but to with c-IAP2 was as a of NF-κB pathway Liu L. S. A. PubMed Scopus Google Scholar). Consistent with this, we found that the NF-κB pathway inhibitor and a protein CHX, the of c-IAP2 protein in TF-1 cells, the effect The of the c-IAP2 protein with the of initiator caspase-8 and effector the caspases are of apoptosis in these cells Interestingly, we found that the of was in or in the presence of TL1A in the of of c-IAP2 by RNA in TF-1 the of c-IAP2 in TL1A and DR3 cell fate were and TF-1 cells by to of the c-IAP2 and of c-IAP2 c-IAP2 production in TF-1 cells induced by but effect the a siRNA, did not c-IAP2 production in these cells, the effect of the c-IAP2 TF-1 cells in the presence of or DR3 agonistic antibody and to a significantly induced the caspase of the cells but were in the of these These that inhibition of c-IAP2 alone greatly sensitized TF-1 cells to TL1A and DR3-induced cell death. The or death of a cell is by and in response to different and of the TNF of with their receptors to cell or death the cellular and the of the ligand and receptor interaction R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2984) Google Scholar). the signaling mechanisms of the death receptors have that members of the NF-κB and caspase are of this and death The these and ultimately the cell fate A. Nat. Rev. Cancer. 2002; 2: 420-430Crossref PubMed Scopus (1099) Google Scholar, 7Baud V. Karin M. Trends Cell Biol. 2001; 11: 372-377Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar, M. A. Nat. 2002; PubMed Scopus Google Scholar). of Fas and DR4 (or triggers apoptosis but not cell these death receptors FADD and Fas not TRADD, RIP, or and is a of NF-κB and the other hand, is a of NF-κB and of its ability to and signaling TNF is a of apoptosis in cells, and programmed cell death the NF-κB pathway or protein is A. Nat. Rev. Cancer. 2002; 2: 420-430Crossref PubMed Scopus (1099) Google Scholar, 7Baud V. Karin M. Trends Cell Biol. 2001; 11: 372-377Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar, M. A. Nat. 2002; PubMed Scopus Google Scholar). this we studied death receptor DR3 to its physiological signal and signaling events as well as to understand the molecular mechanisms its cell fate We human erythroleukemic cell TF-1 as our these cells express DR3 and activation and of apoptosis to TL1A as human activated T cells (1Migone T.S. Zhang J. Luo X. Zhuang L. Chen C. Hu B. Hong J.S. Perry J.W. Chen S.F. Zhou J.X. Cho Y.H. Ullrich S. Kanakaraj P. Carrell J. Boyd E. Olsen H.S. Hu G. Pukac L. Liu D. Ni J. Kim S. Gentz R. Feng P. Moore P.A. Ruben S.M. Wei P. Immunity. 2002; 16: 479-492Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). Although human T cells express of the human T cell including and have detectable levels of DR3 J. M. P. J. J. Moore G. A. PubMed Scopus Google Scholar). Zhuang and P. Our study that TL1A-DR3 signaling in TF-1 cells in the formation of signaling containing TRADD, TRAF2, and RIP and the activation of the NF-κB and pathways. RIP and are in NF-κB and activation, respectively, is to that functions in TL1A-induced NF-κB and The signaling molecules of and RIP that the activation of these pathways, in the and p38 pathways, to to we did not of FADD or procaspase-8 association with the DR3 signaling in TF-1 cells. that in these cells the DR3 TRADD a complex with and RIP with FADD or However, the by eliminating the did not the nor did FADD association TL1A and P. mechanisms to FADD and procaspase-8 binding to TRADD either by molecules this association or preferentially the and RIP binding to The that the presence of a NF-κB inhibitor or a protein inhibitor induced apoptosis that these molecules have and that their the association of FADD and FADD and caspase-8 are for DR3-induced apoptosis A. M. A. PubMed Scopus Google Scholar, M. V. N. J.S. D. V.M. D. P. D. Immunity. Full Text Full Text PDF PubMed Scopus Google the of of these to DR3 an but important cell in TF-1 cells. that DR3-mediated NF-κB and activation of apoptosis in these cells. NF-κB and activation in activation and protein these signaling events the cell of death in TF-1 cells. to seen these mechanisms to human T cells and express DR3 but to of DR3 A. A. J. M.J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). Although DR3 in the a crucial of DR3 in apoptosis, the lymphocyte are not is that different molecular mechanisms T cells in to DR3 in NF-κB have that this factor is a anti-apoptotic in signaling A. D. Scopus Google Scholar, Karin M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, Trends Cell Biol. Full Text PDF PubMed Scopus Google Scholar, M. A. Nat. 2002; PubMed Scopus Google Scholar). NF-κB to TNF and apoptosis, cells were Our study this by that NF-κB plays a anti-apoptotic in TL1A-DR3 The of a inhibitor to or TF-1 cells is to induce caspase activation and programmed cell death. and of are for the of cell for TF-1 cells. These as for TRADD and FADD binding and/or for other death including initiator and effector of this protein the apoptosis caspase was seen 3 The for in apoptosis is anti-apoptotic were for and p38 S. Curr. Mol. Med. 2001; 1: 317-324Crossref PubMed Scopus (56) Google Scholar, M. A. Nat. 2002; PubMed Scopus Google Scholar). However, the that activation is of TNF or apoptosis Karin M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. A. C. M. PubMed Scopus Google Scholar). with this, our study that of the a anti-apoptotic in cell death in TF-1 cells. are to the of these in TL1A-DR3 is known that NF-κB its anti-apoptotic through the of anti-apoptotic These c-IAP2, c-FLIP, TRAF2, XIAP, Bcl-2, and Among them, are the best studied. apoptosis induced by the and the death death pathways through binding and of death 2000; Scholar). Interestingly, we found that in TF-1 cells, TL1A and the of c-IAP2 a of NF-κB Liu L. S. A. PubMed Scopus Google Scholar). of c-IAP2 by RNA interference sensitized these cells to and cell death a of c-IAP2 in DR3-mediated cell fate in TF-1 cells. c-IAP2 has found to NF-κB activation Liu L. S. A. PubMed Scopus Google Scholar). NF-κB signal transduction to signal and ultimately cell The effect of TL1A the of other including c-FLIP, XIAP, TRAF2, Bcl-2, and is not However, a of was seen TL1A was used with or suggesting that a either or with c-IAP2, in the apoptosis. The mechanisms by which c-IAP2 apoptosis The by this study that DR3 is to TNFR1 signaling for signal transduction and molecular mechanisms in cell fate We Wei and for and We and for the and