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) an d other cytokines. IL-12-induced organ alterations are reported for mi ce and the pathogenetic role of IFN-gamma is investigated by the use o f mice deficient in the IFN-gamma receptor (IFN-gamma R(-/-)). IL-12 c aused a rapid infiltration of liver and splenic red pulp with activate d macrophages; this and increased NK cells resulted in a fivefold incr ease of splenic weight in wild-type mice. Splenomegaly was associated with myelosuppression and decreasing peripheral leukocyte counts. IL-1 2-induced changes in wild-type mice were associated with markedly incr eased IFN-gamma serum levels and up-regulation of major histocompatibi lity complex (MHC) class I and II expression in various epithelia. IL- 12 induced a qualitatively similar macrophage infiltration in IFN-gamm a R(-/-) mice, less marked splenomegaly (to 2 x normal), and no MHC up regulation. Strikingly increased vascular endothelial intercellular ad hesion molecule-1 expression was apparent in both IFN-gamma R(-/-) and IFN-gamma R(+/+) mice. Restricted to mutant mice was a severe, invari ably lethal, interstitial, and perivascular pulmonary macrophage infil tration with diffuse pulmonary edema. Extensive quantitative reverse t ranscriptase polymerase chain reaction analysis revealed an increase o f only IL-6 and IL-10 pulmonary gene transcripts in IFN-gamma R(-/-) m ice compared with wild-type mice. IL-12-induced myelosuppression is du e to IFN-gamma-release from NK cells and T cells, and is associated wi th macrophage activation and distinct MHC class I and II antigen upreg ulation. The pulmonary pathology in IFN-gamma R(-/-) mice, however, re veals a toxic potential for IL-12 and suggests that endogenous IFN-gam ma plays a protective role in preventing fatal pulmonary disease in th ese mice.