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  4. Involvement of Ifn-Gamma in Bacillus Calmette-Guerin-Induced but Not in Tumor-Induced Sensitization to Tnf-Induced Lethality
 
research article

Involvement of Ifn-Gamma in Bacillus Calmette-Guerin-Induced but Not in Tumor-Induced Sensitization to Tnf-Induced Lethality

Cauwels, A.
•
Brouckaert, P.
•
Grooten, J.
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1995
Journal of Immunology

In healthy mice, murine (m) TNF is fairly lethal, whereas human (h) TNF (a selective murine TNF-R55 agonist) is rather harmless. However, we and others observed that mice suffering from a bacterial infection, such as Bacillus Calmette-Guerin (BCG), or bearing i.m. some types of tumor, develop a hypersensitivity to the IL-6-inducing and lethal properties of hTNF. This is a cardinal problem as it severely limits the potential use of hTNF-R55-specific agonists for systemic treatment of human cancer. Using mice carrying a targeted disruption in the gene encoding the IFN-gamma receptor (IFN-gamma R(0/0)), we here report that endogenous IFN-gamma plays a crucial role in the development of TNF hypersensitivity during BCG infection. Indeed, both the lethality and the IL-6 induced by hTNF were drastically reduced in IFN-gamma R(0/0) mice as compared with control mice. These results demonstrate that the enhancement of TNF effects is at least an equally important mechanism by which IFN-gamma contributes to BCG-induced hypersensitivity as the previously described augmentation of TNF production. Experiments in athymic nude mice, either depleted of NK cells or not, revealed that the latter cell population is an important source of the sensitizing IFN-gamma during BCG infection. In contrast, IFN-gamma R(0/0) mice were as susceptible as control mice to the sensitizing effects of tumors. mTNF, which interacts with both mTNF-R55 and mTNF-R75 and causes lethality on its own, is as toxic in IFN-gamma R(0/0) mice as in wt control mice; this means that TNF-induced IFN-gamma does not play a role in mTNF-induced lethality.

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Type
research article
Author(s)
Cauwels, A.
Brouckaert, P.
Grooten, J.
Huang, S.
Aguet, M.  
Fiers, W.
Date Issued

1995

Published in
Journal of Immunology
Volume

154

Issue

6

Start page

2753

End page

2763

Note

State Univ Ghent,Molec Biol Lab,B-9000 Ghent,Belgium Univ Zurich,Dept Molec Biol 1,Zurich,Switzerland

Editorial or Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
UPAGU  
Available on Infoscience
December 12, 2007
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/15445
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