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Shared actions of endotoxin and taxol on TNF receptors and TNF release
A H Ding1, F Porteu, E Sanchez
1Department of Medicine, Cornell University Medical College, New York, NY 10021.
Abstract:
Bacterial lipopolysaccharide (LPS) exerts profound effects on mammalian hosts in part by inducing macrophages to release tumor necrosis factor-alpha (TNF-alpha); the mechanisms involved are unresolved. The microtubule stabilizer taxol shared two actions of LPS on macrophages: it rapidly decreased TNF-alpha receptors and triggered TNF-alpha release. Both actions of taxol were absent in LPS-hyporesponsive C3H/HeJ mice. In recombinant inbred mice, the genes controlling responses to LPS and to taxol were closely linked. Dexamethasone blocked release of TNF-alpha by both stimuli but did not block the decrease in TNF-alpha receptors. Thus, a protein associated with microtubules may be a cellular target of LPS.
Insights
Bacterial lipopolysaccharide (LPS) triggers tumor necrosis factor-alpha (TNF-alpha) release by decreasing TNF-alpha receptors on macrophages. This effect, shared by taxol, suggests a microtubule-associated protein as a cellular target of LPS.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Bacterial lipopolysaccharide (LPS) significantly impacts mammalian hosts by stimulating macrophages to release tumor necrosis factor-alpha (TNF-alpha).
- The precise molecular mechanisms underlying LPS-induced TNF-alpha release and receptor modulation remain incompletely understood.
- Understanding these pathways is crucial for developing targeted immunomodulatory therapies.
Purpose of the Study:
- To investigate the cellular mechanisms by which LPS induces TNF-alpha release from macrophages.
- To identify potential cellular targets of LPS action by comparing its effects with known cellular modulators.
- To elucidate the role of microtubule-associated proteins in LPS-mediated immune responses.
Main Methods:
- Comparative analysis of LPS and taxol (a microtubule stabilizer) effects on macrophage TNF-alpha receptor levels and TNF-alpha release.
- Utilizing LPS-hyporesponsive C3H/HeJ mice to assess genetic control of responses.
- Employing recombinant inbred mouse strains to map genes controlling responses to LPS and taxol.
- Investigating the effect of dexamethasone on LPS- and taxol-induced responses.
Main Results:
- Taxol mimicked LPS by rapidly decreasing TNF-alpha receptors and triggering TNF-alpha release in macrophages.
- These taxol-induced effects were absent in LPS-hyporesponsive C3H/HeJ mice, indicating a shared genetic pathway.
- Genes controlling responses to LPS and taxol were found to be closely linked in recombinant inbred mice.
- Dexamethasone inhibited TNF-alpha release induced by both LPS and taxol but did not affect the decrease in TNF-alpha receptors.
Conclusions:
- A protein associated with microtubules is implicated as a cellular target of bacterial lipopolysaccharide (LPS).
- The findings suggest that LPS-induced TNF-alpha release involves modulation of microtubule-associated proteins.
- This research provides novel insights into the molecular mechanisms of LPS-macrophage interactions and potential therapeutic targets.