Galectin-9 ameliorates Con A-induced hepatitis by inducing CD4(+)CD25(low/int) effector T-Cell apoptosis and increasing regulatory T cell number

PLoS One. 2012;7(10):e48379. doi: 10.1371/journal.pone.0048379. Epub 2012 Oct 31.

Abstract

Background: T cell-mediated liver damage is a key event in the pathogenesis of many chronic human liver diseases, such as liver transplant rejection, primary biliary cirrhosis, and sclerosing cholangitis. We and other groups have previously reported that galectin-9, one of the β-galactoside binding animal lectins, might be potentially useful in the treatment of T cell-mediated diseases. To evaluate the direct effect of galectin-9 on hepatitis induced by concanavalin A (Con A) administration in mice and to clarify the mechanisms involved, we administered galectin-9 into mice, and evaluated its therapeutic effect on Con A-induced hepatitis.

Methodology/principal findings: Galectin-9 was administrated i.v. to Balb/c mice 30 min before Con A injection. Compared with no treatment, galectin-9 pretreatment significantly reduced serum ALT and AST levels and improved liver histopathology, suggesting an ameliorated hepatitis. This therapeutic effect was not only attributable to a blunted Th1 immune response, but also to an increased number in regulatory T cells, as reflected in a significantly increased apoptosis of CD4(+)CD25(low/int) effector T cells and in reduced proinflammatory cytokine levels.

Conclusion/significance: Our findings constitute the first preclinical data indicating that interfering with TIM-3/galectin-9 signaling in vivo could ameliorate Con A-induced hepatitis. This strategy may represent a new therapeutic approach in treating human diseases involving T cell activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • CD4 Lymphocyte Count
  • Concanavalin A / adverse effects*
  • Cytokines / biosynthesis
  • Galectins / pharmacology*
  • Galectins / therapeutic use
  • Hepatitis / drug therapy*
  • Hepatitis / etiology
  • Hepatitis / immunology*
  • Hepatitis / pathology
  • Interleukin-2 Receptor alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Cytokines
  • Galectins
  • Interleukin-2 Receptor alpha Subunit
  • Concanavalin A

Grant support

This work was funded by Natural Science Foundation of the Anhui Higher Education Institutions of China (KJ2011B191, KJ2011B198) and The Foundation of Introducing Talents of Yijishan Hospital (YJRC2009003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.