Role of interferon-gamma in interleukin 12-induced pathology in mice.
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.
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008285:Major Histocompatibility Complex / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000097:blood; D011654:Pulmonary Edema / Q000209:etiology; D017471:Receptors, Interferon / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor