Galectin-3 deficiency prevents concanavalin A-induced hepatitis in mice.
We used concanavalin A (Con A)-induced liver injury to study the role of galectin-3 (Gal-3) in the induction of inflammatory pathology and hepatocellular damage. We tested susceptibility to Con A-induced hepatitis in galectin-3-deficient (Gal-3(-/-)) mice and analyzed the effects of pretreatment with a selective inhibitor of Gal-3 (TD139) in wild-type (WT) C57BL/6 mice, as evaluated by a liver enzyme test, quantitative histology, mononuclear cell (MNC) infiltration, cytokine production, intracellular staining of immune cells, and percentage of apoptotic MNCs in the liver. Gal-3(-/-) mice were less sensitive to Con A-induced hepatitis and had a significantly lower number of activated lymphoid and dendritic cells (DCs) in the liver. The level of tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin (IL)-17 and -4 in the sera and the number of TNFα-, IFNγ-, and IL-17- and -4-producing cluster of differentiation (CD)4(+) cells as well as IL-12-producing CD11c(+) DCs were lower, whereas the number of IL-10-producing CD4(+) T cells and F4/80(+) macrophages were significantly higher in livers of Gal-3(-/-) mice. Significantly higher percentages of late apoptotic Annexin V(+) propidium-idodide(+) liver-infiltrating MNCs and splenocytes were observed in Gal-3(-/-) mice, compared to WT mice. Pretreatment of WT C57BL/6 mice with TD139 led to the attenuation of liver injury and milder infiltration of IFNγ- and IL-17- and -4-producing CD4(+) T cells, as well as an increase in the total number of IL-10-producing CD4(+) T cells and F4/80(+) CD206(+) alternatively activated macrophages and prevented the apoptosis of liver-infiltrating MNCs.


CONCLUSIONS
Gal-3 plays an important proinflammatory role in Con A-induced hepatitis by promoting the activation of T lymphocytes and natural killer T cells, maturation of DCs, secretion of proinflammatory cytokines, down-regulation of M2 macrophage polarization, and apoptosis of MNCs in the liver.
Center for Molecular Medicine and Stem Cell Research, Faculty of Medicine, University of Kragujevac, Kragujevac, Serbia.
Vladislav
V
Volarevic
Marija
M
Milovanovic
Biljana
B
Ljujic
Nada
N
Pejnovic
Nebojsa
N
Arsenijevic
Ulf
U
Nilsson
Hakon
H
Leffler
Miodrag L
ML
Lukic
D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D003208:Concanavalin A / Q000633:toxicity*; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology; D037502:Galectin 3 / Q000172:deficiency / Q000502:physiology*; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D016207:Cytokines; D037502:Galectin 3; D003208:Concanavalin A