Article: article from journal or magazin.
Role of interferon-gamma in interleukin 12-induced pathology in mice.
American Journal of Pathology
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.
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
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