Endogenous membrane tumor necrosis factor (TNF) is a potent amplifier of TNF receptor 1-mediated apoptosis.
The heat shock protein 90 (Hsp-90) inhibitor, geldanamycin, and the proteasome inhibitor, MG-132, both inhibited tumor necrosis factor receptor 1 (TNF-R1)- but not TRAIL-induced apoptosis in Kym-1 cells, suggesting that TNF-R1-induced cell death is dependent on NF-kappaB activation in this model. Triggering of TNF-R1 by agonistic antibodies led to cell-type specific induction of endogenous TNF and apoptosis, the latter of which was abrogated by neutralizing TNF specific antibodies. TNF-R1-stimulated cells expressed TNF mainly in a cell-associated form, suggesting that the endogenously produced TNF act in its membrane-bound form. Geldanamycin failed to inhibit apoptosis induction by a combination of agonistic TNF-R1- and TNF-R2-specific antibodies, indicating that both TNF receptors co-operate in TNF-R1-triggered apoptosis in Kym-1 cells. Thus, TNF-R1 stimulation can elicit a strong and rapid apoptotic response via induction of membrane TNF and subsequent cooperation of TNF-R1 and TNF-R2. Moreover, we give evidence that this mechanism circumvents the need of the prolonged presence of exogenous soluble TNF for TNF-R1-mediated apoptosis induction.
Weingärtner
Monika
M
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
Siegmund
Daniela
D
Schlecht
Ulrich
U
Fotin-Mleczek
Mariola
M
Scheurich
Peter
P
Wajant
Harald
H
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011809:Quinones; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C001277:geldanamycin