Role of interferon-gamma in interleukin 12-induced pathology in mice.

Details

Serval ID
serval:BIB_96AA96538C91
Type
Article: article from journal or magazin.
Collection
Publications
Title
Role of interferon-gamma in interleukin 12-induced pathology in mice.
Journal
American Journal of Pathology
Author(s)
Car B.D., Eng V.M., Schnyder B., LeHir M., Shakhov A.N., Woerly G., Huang S., Aguet M., Anderson T.D., Ryffel B.
ISSN
0002-9440 (Print)
ISSN-L
0002-9440
Publication state
Published
Issued date
1995
Volume
147
Number
6
Pages
1693-1707
Language
english
Abstract
Interleukin 12 (IL-12) activates natural killer (NK) and T cells with the secondary synthesis and release of interferon-gamma (IFN-gamma) and other cytokines. IL-12-induced organ alterations are reported for mice and the pathogenetic role of IFN-gamma is investigated by the use of mice deficient in the IFN-gamma receptor (IFN-gamma R-/-). IL-12 caused a rapid infiltration of liver and splenic red pulp with activated macrophages; this and increased NK cells resulted in a fivefold increase of splenic weight in wild-type mice. Splenomegaly was associated with myelosuppression and decreasing peripheral leukocyte counts. IL-12-induced changes in wild-type mice were associated with markedly increased IFN-gamma serum levels and up-regulation of major histocompatibility complex (MHC) class I and II expression in various epithelia. IL-12 induced a qualitatively similar macrophage infiltration in IFN-gamma R-/- mice, less marked splenomegaly (to 2 x normal), and no MHC upregulation. Strikingly increased vascular endothelial intercellular adhesion molecule-1 expression was apparent in both IFN-gamma R-/- and IFN-gamma R+/+ mice. Restricted to mutant mice was a severe, invariably lethal, interstitial, and perivascular pulmonary macrophage infiltration with diffuse pulmonary edema. Extensive quantitative reverse transcriptase polymerase chain reaction analysis revealed an increase of only IL-6 and IL-10 pulmonary gene transcripts in IFN-gamma R-/- mice compared with wild-type mice. IL-12-induced myelosuppression is due to IFN-gamma-release from NK cells and T cells, and is associated with macrophage activation and distinct MHC class I and II antigen upregulation. The pulmonary pathology in IFN-gamma R-/- mice, however, reveals a toxic potential for IL-12 and suggests that endogenous IFN-gamma plays a protective role in preventing fatal pulmonary disease in these mice.
Keywords
Animals, Antigens, CD/metabolism, Bone Marrow/drug effects, Bone Marrow/pathology, Interferon-gamma/biosynthesis, Interferon-gamma/drug effects, Interleukin-10/biosynthesis, Interleukin-12/pharmacology, Liver/drug effects, Liver/metabolism, Lung/drug effects, Lung/metabolism, Macrophages/drug effects, Major Histocompatibility Complex/drug effects, Major Histocompatibility Complex/genetics, Mice, Mice, Inbred Strains, Mice, Mutant Strains, Nitric Oxide/blood, Pulmonary Edema/etiology, Receptors, Interferon/metabolism, Spleen/drug effects, Spleen/metabolism, Tumor Necrosis Factor-alpha/analysis, Up-Regulation/drug effects
Pubmed
Web of science
Create date
28/01/2008 11:36
Last modification date
20/08/2019 14:58
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