Repeated concanavalin A challenge in mice induces an interleukin 10-producing phenotype and liver fibrosis

Hepatology. 2000 Feb;31(2):381-90. doi: 10.1002/hep.510310218.

Abstract

Weekly injections of Concanavalin A (Con A) were performed in BALB/c mice to evaluate the pattern of cytokine production and liver injury. High serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), IL-4, and interferon gamma (IFN-gamma) were found in the serum after the first 2 injections of Con A but rapidly decreased from the third injection. Conversely, IL-10 serum levels after repeated Con A challenge increased by 7 times from week 1 to 20. In vivo depletion studies indicated that CD4(+) T cells are essential in IL-10 production. Hepatocyte necrosis was only observed after the first injections of Con A whereas centrilobular inflammatory infiltrates persisted up to 20 weeks. Perisinusoidal liver fibrosis was also increasingly detected in BALB/c mice, whereas no fibrous change was observed in nude mice after 6 weeks of Con A challenge. The number of stellate cells, detected by immunostaining, increased after 20 weeks of Con A injections. Liver cytokine messenger RNA (mRNA) expression after 20 weeks showed expression of transforming growth factor beta1 (TGF-beta1), IL-10, and IL-4 whereas IL-2 was no more expressed. The present study shows that mice repeatedly injected with Con A develop liver fibrosis. The cytokine-release pattern observed after 1 injection of Con A is rapidly shifted towards an immunomodulatory phenotype characterized by the systemic production of large amounts of IL-10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Concanavalin A / administration & dosage*
  • Concanavalin A / pharmacology
  • Drug Administration Schedule
  • Female
  • Interleukin-10 / biosynthesis*
  • Liver / pathology
  • Liver Cirrhosis, Experimental / chemically induced*
  • Liver Cirrhosis, Experimental / mortality
  • Mice
  • Mice, Inbred BALB C
  • Necrosis
  • Phenotype
  • Time Factors

Substances

  • Concanavalin A
  • Interleukin-10