Massive liver necrosis after provocation of imbalance between Th1 and Th2 immune reactions in osteopontin transgenic mice

J Gastroenterol. 2004 Sep;39(9):867-72. doi: 10.1007/s00535-004-1403-0.

Abstract

Background: Massive liver necrosis can develop as a consequence of imbalance between T-helper (Th)1 and Th2 immune reactions in the liver. Osteopontin is a glycoprotein secreted for the initiation of the Th1 immune reaction, as well as for extracellular matrix formation and calcium deposition in the bone and kidney. Osteopontin is overexpressed in Kupffer cells, macrophages, and stellate cells activated in injured livers. We established transgenic mice expressing osteopontin exclusively in hepatocytes, using a vector containing human serum amyloid P component promoter. The relation of Th1/Th2 immune imbalance to massive liver necrosis was studied using these transgenic mice.

Methods: Transgenic mice and C27BL/6 mice, wild-type controls of the transgenic mice, were given an intravenous injection of concanavalin-A, and the histological extent of liver injuries and plasma cytokine levels were evaluated.

Results: When the transgenic mice received concanavalin-A, massive necrosis and mononuclear cell infiltration developed in the liver, the extent of which was greater in the female mice than in the male mice. This treatment produced minimal liver injury and focal liver necrosis in male and female C57BL/6 mice. In these transgenic and control mice, plasma concentrations of interleukin (IL)-10 and interferon (IFN)-gamma were increased after concanavalin-A treatment. However, the upregulation of plasma IL-10 concentration was smaller in the male and female transgenic mice than in the control mice, and the upregulation of the IFN-gamma concentration was greater in the female transgenic mice than in the female control mice.

Conclusions: Th1 and Th2 immune reactions were deranged after concanavalin-A treatment, with Th1 immunity predominating in transgenic mice expressing osteopontin in hepatocytes; this immunological imbalance may contribute to massive liver necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Concanavalin A / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Immunity, Cellular / immunology*
  • Liver / immunology*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Necrosis
  • Osteopontin
  • Sialoglycoproteins / metabolism
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*
  • Up-Regulation / immunology

Substances

  • Cytokines
  • SPP1 protein, human
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • Osteopontin
  • Concanavalin A