title: TL1A-induced NF-kappaB 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. 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-kappaB 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-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB 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-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB 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.
authors.affiliation: Department of Antibody Development, Human Genome Sciences, Inc., Rockville, Maryland 20833, USA.
authors.forename: Leng
authors.initials: L
authors.lastname: Wen
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.forename: Xia
authors.initials: X
authors.lastname: Luo
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000911:Antibodies, Monoclonal; D029681:Arabidopsis Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011506:Proteins; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011994:Recombinant Proteins; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases