Role of interferon-γ 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-T (IFN-γ) and other cytokines. IL-12-induced organ alterations are reported for mice and the pathogenetic role of IFN-γ is investigated by the use of mice deficient in the IFN-γ receptor (IFN-γR(-/-)). 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-γ serum levels and upregulation of major histocompatibility complex (MHC) class I and II expression in various epithelia. IL-12 induced a qualitatively similar macrophage infiltration in IFN-γR(-/-) 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-γR(-/-) and IFN- γR(+/+) 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-γR(-/-) mice compared with wild-type mice. IL-12- induced myelosuppression is due to IFN-γ-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-γR(-/-) mice, however, reveals a toxic potential for IL-12 and suggests that endogenous IFN-γ plays a protective role in preventing fatal pulmonary disease in these mice.