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- J Bigda
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- I Beletsky
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- C Brakebusch
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- Y Varfolomeev
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- H Engelmann
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- H Holtmann
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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- D Wallach
- Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.
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<jats:p>Whereas there is ample evidence for involvement of the p55 tumor necrosis factor (TNF) receptor (p55-R) in the cytocidal effect of TNF, the role of the p75 TNF receptor (p75-R) in this effect is a matter of debate. In this study, we probed the function of p75-R in cells sensitive to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross-linking by the Abs; (c) occurred in HeLa cells, but not in A9 cells transfected with human p75-R or in HeLa cells expressing cytoplasmically truncated p75-R mutants, indicating that it involves cell-specific activities of the intracellular domain of the receptor; (d) was synergistic with the cytocidal effect of Abs against p55-R. Moreover, it seemed to reverse induced desensitization to the cytocidal effect of anti p55-R Abs, suggesting that it involves mechanisms different from those of the signaling by the p55 TNF-R. In addition, the Abs affected the response to TNF in a way that does not involve the signaling activity of p75-R. These effects: (a) could be observed also in cells in which only p55-R signaled for the cytocidal effect; (b) were not dependent on receptor cross-linking by the Abs; (c) varied according to the site at which the Abs bound to the receptor; and (d) were correlated inversely with the effects of the Abs on TNF binding to p75-R. That is, Abs binding to the membrane-distal part of the receptor's extracellular domain displaced TNF from the p75 receptor and enhanced cytocidal effect, whereas Abs that bind to the membrane-proximal part of the extracellular domain--a region at which a conformational change seems to take place upon TNF binding--decreased the dissociation of TNF from p75-R and inhibited its cytocidal effect. The above findings suggest that p75-R contributes to the cytocidal effect of TNF both by its own signaling and by regulating the access of TNF to p55-R.</jats:p>
収録刊行物
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- The Journal of experimental medicine
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The Journal of experimental medicine 180 (2), 445-460, 1994-08-01
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1362825894766240256
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- NII論文ID
- 30017430892
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- NII書誌ID
- AA00697559
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- ISSN
- 15409538
- 00221007
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