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Continuous autotropic signaling by membrane-expressed tumor necrosis factor
1Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
The Journal of Biological Chemistry
|June 11, 1999
Summary
Membrane-integrated Tumor Necrosis Factor (TNF) can create self-signaling loops. This constitutive autotropic signaling, independent of cell contact, impacts cellular responses and may be crucial in immune cells.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tumor Necrosis Factor (TNF) has membrane-bound and soluble forms.
- Autocrine/juxtacrine feedback loops involving TNF are known.
- The role of membrane TNF in these regulatory circuits was unclear.
Purpose of the Study:
- To investigate if membrane-integrated TNF can mediate autotropic signaling.
- To determine the functional consequences of constitutive membrane TNF signaling.
Main Methods:
- Utilized HeLa cells expressing a permanently membrane-integrated TNF mutant.
- Assessed cell surface TNF receptor complexes, NF-kappaB activation, and p38 MAPK activity.
- Evaluated sensitivity to cycloheximide and interferon-gamma, and apoptosis induction.
Main Results:
- HeLa cells with membrane TNF constitutively expressed TNF-receptor complexes.
- These cells showed sustained NF-kappaB activation and p38 MAPK activity, producing high IL-6.
- Transfected cells exhibited heightened sensitivity to cycloheximide/interferon-gamma and inducible apoptosis, independent of cell contact.
Conclusions:
- Autotropic signaling loops mediated by membrane TNF can occur.
- This signaling is critical for constitutive cellular activation and response.
- These findings are relevant for cells expressing both TNF and its receptors, like immune cells.