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

Am J Pathol. 1995 Dec;147(6):1693-707.

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.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / drug effects*
  • Interferon-gamma / physiology
  • 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

Substances

  • Antigens, CD
  • Receptors, Interferon
  • Tumor Necrosis Factor-alpha
  • interferon gamma receptor
  • Interleukin-10
  • Interleukin-12
  • Nitric Oxide
  • Interferon-gamma