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ENDOTOXIN TOLERANCE IMPAIRS A PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN REGULATING TUMOUR NECROSIS FACTOR RELEASE BY MACROPHAGES FROM TUMOUR-BEARING RATS
The aim of this work was to study whether a G-protein regulates lipopolysaccharide (LPS) induced TNF-α production in tumour-bearing rat peritoneal macrophages differently to in normal rats. We also investigated whether a state of `early endotoxin tolerance' affects LPS induced TNF-α release via...
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Published in: | Pharmacological research 1996-03, Vol.33 (3), p.203-209 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that cite this one |
Online Access: | Get full text |
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Summary: | The aim of this work was to study whether a G-protein regulates lipopolysaccharide (LPS) induced TNF-α production in tumour-bearing rat peritoneal macrophages differently to in normal rats. We also investigated whether a state of `early endotoxin tolerance' affects LPS induced TNF-α release via a G-protein-mediated phenomenon.
LPS-stimulated (50μgml
−1of
Salmonella enteritidisLPS) TNF-α release was investigated in peritoneal macrophages harvested from both normal rats and tumour-bearing rats. Cholera toxin (10, 100 and 1000ngml
−1) did not significantly modify LPS-induced TNF-α release. In contrast pertussis toxin (0.1, 1.0 and 10ngml
−1) significantly increased LPS-induced TNF-α release and inhibited LPS-stimulated prostaglandin E
2(PGE
2) production in both normal rat macrophages and tumour-bearing rat macrophages. Pertussis toxin effects on these LPS responses were correlated with a pertussis-toxin-mediated ADP-ribosylation of a 41kDa protein(s).
The LPS-mediated responses were significantly greater in macrophages from tumour-bearing rats than in macrophages from normal rats. PGE
2(10
−9, 10
−8and 10
−7
M) suppressed LPS-induced TNF-α production in a dose-dependent fashion.
A state of `early endotoxin tolerance' was then induced in tumour-bearing rats by a single intravenous injection of 125μgrat
−1of LPS, and experiments were performed on peritoneal macrophages harvested 24h after LPS injection. In tolerant macrophages pertussis toxin induced an increase in LPS-stimulated TNF-α release and an inhibition in LPS-stimulated PGE
2release significantly lower than in macrophages harvested from non-tolerant tumour bearing rats. Our results suggest that a pertussis-toxin-sensitive G-protein may serve to regulate the synthesis of TNF-α in rat peritoneal macrophages and that the activity of this pertussis-sensitive G-protein is increased in macrophages from tumour-bearing rats. Furthermore, our experiments would indicate that a `state of endotoxin tolerance', caused by altering the function of presumably a G
i-protein, may exert beneficial effects on the functions of macrophages in tumour-bearing rats. |
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ISSN: | 1043-6618 1096-1186 |
DOI: | 10.1006/phrs.1996.0028 |