7B). To test the role of the host genetic background in this process, we transferred the Gal-1–KO mutation into the FVB strain and challenged the Gal-1–KO/FVB mice with ConA. Surprisingly, the extent of injury in the Gal-1–KO/FVB livers following the ConA challenge was similar to that in FVB WT controls (Fig. 7C). This result was also confirmed with the use of a 2-fold higher ConA dose (not shown). We found that the Gal-1 transcript was up-regulated 8 hours after the ConA injection in both WT strains (Fig. 7D). These results demonstrate that endogenous Gal-1 selectively protects against ConA-induced liver injury in the B6 strain but not in the FVB strain. To uncover the molecular

mechanisms for the increased sensitivity of Gal-1–KO/B6 mutants to ConA-induced INCB024360 datasheet hepatitis, we tested Midostaurin the expression of selected genes 8 hours after ConA injection (Fig. 7E,F). The most significant difference between the experimental groups was

the increased expression of the proinflammatory cytokines Tnfa, Il-2, and chemokine (C-X-C motif) ligand 2 (Cxcl2) and the anti-inflammatory secretory leukocyte peptidase inhibitor (Slpi) in Gal-1–KO/B6 livers (Fig. 7F). The Mdr2-KO mouse model of inflammation-induced HCC mimics human disease in terms of both prolonged chronic hepatitis preceding tumor development1 and aberrant gene expression in tumors.2 The phenotypic manifestations of the Mdr2-KO mutation are strain-dependent. Initially, the mutation was introduced into the 129/OlaHsd strain,15 and this resulted in a highly enlarged (up to 8-fold) nodular liver already at the age of 6 months.1 The Mdr2-KO/FVB mice have a mildly increased liver/body index (approximately 1.6-fold in males) that does not change significantly between 3 and 12 months of

age.4 Now, we transferred the Mdr2-KO mutation into the B6 genetic background and demonstrated significantly retarded HCC development and inhibition of chronic hepatitis between 2 and 3 months of age in Mdr2-KO/B6 males. Multiple genes involved in the control of immune/inflammatory responses were up-regulated mainly in the Mdr2-KO/FVB strain, and this was in agreement with the higher infiltration of immune cells. One of these genes, Lgals1, encodes Gal-1, an endogenous lectin that is widely expressed in epithelial and immune cells and however acts both extracellularly and intracellularly by modulating innate and adaptive immunity.16, 17 In addition, Gal-1 is a key mediator of the immunosuppressive activity of regulatory T cells.18 Gal-1 overexpression in many types of tumors and/or surrounding tissues promotes tumor progression through multiple mechanisms: the inhibition of antitumor immunity,16, 19 the promotion of Ras activation,20 the stimulation of tumor angiogenesis,21, 22 and the attenuation of NF-κB activation.23 Gal-1 is overexpressed in human HCC24, 25 and in the Mdr2-KO liver.