1A). The dnTGFβRII mice had clinical manifestations of inflammatory bowel disease, including diarrhea and loss of body weight. These changes were not seen in dnTGF-βRII IL-6−/− mice (Fig. 1B). Histologic examination of the large bowel of dnTGFβRII mice disclosed chronic inflammation and granulomatous reactions, including the presence

of multinucleated giant cells (Fig. 1C). There was chronic and active inflammation with cryptitis and crypt abscess throughout the large intestine of dnTGFβRII mice. Importantly, there were no detectable histologic abnormalities in the intestinal tissues of the dnTGF-βRII IL-6−/− mice. Unlike the clinical improvement in the colon, dnTGF-βRII IL-6−/− mice demonstrate a significant (P < 0.05) increase in absolute number of hepatic mononuclear cells as compared CB-839 cell line with dnTGF-βRII control mice at 22-24 weeks of age (Fig. 2). Flow cytometric data demonstrated that the absolute number of TCRβ+NK1.1− T cell lineages and CD19+ B cells are also significantly (P < 0.01) elevated in the liver of dnTGF-βRII find more IL-6−/− mice, associated with a significant increase in the absolute cell number of CD44-expressing T cells. Furthermore, there was a considerable increase (graded moderate to severe) in bile ductular proliferation in liver sections of dnTGF-βRII IL-6−/− mice (Fig. 3A) as compared with liver sections

from dnTGF-βRII mice that showed mild to moderate bile ductular proliferation (Fig. 3B). A characteristic histopathological feature of human PBC is granuloma formation. Indeed, dnTGFβRII mice frequently

demonstrate hepatic granuloma formation (Fig. 4). Interestingly, no granulomas were detected AZD9291 ic50 in dnTGF-βRII IL-6−/− mice. All histologic evaluations were performed in a blinded fashion. The level of serum TNF-α was significantly decreased in dnTGFβRII IL-6−/− mice compared to dnTGFβRII mice (19.5 ± 2.9 pg/mL versus 28.5 ± 2.2 pg/mL; P < 0.05). There were no significant differences in serum IFNγ (dnTGFβRII IL-6−/− mice: 10.3 ± 1.4 pg/mL versus dnTGFβRII mice: 19.3 ± 5.0 pg/mL; P > 0.05) or serum IL-12p40 (dnTGFβRII IL-6−/− mice: 664.0 ± 91.4 pg/mL versus dnTGFβRII mice: 865.7 ± 223.5 pg/m; P > 0.05) in the two groups of mice (Fig. 5A). Although not statistically significant, the levels of both IFN-γ and IL-12p40 were decreased in the serum of dnTGFβRII IL-6−/− compared to dnTGFβRII mice. The levels of IL-12p40 in liver were comparable between dnTGFβRII IL-6−/− and dnTGFβRII mice (Fig. 5A,B). However, the levels of hepatic TNF-α and IFN-γ were significantly (P < 0.05) increased in dnTGFβRII IL-6−/− mice compared to dnTGFβRII mice (Fig. 5B). There was also a significant decrease (P < 0.01) in serum titers of AMAs in dnTGFβRII IL-6−/− mice (0.20 ± 0.02 at OD 450 nm; n = 8) compared to the control dnTGFβRII mice (0.47 ± 0.06 at OD 450 nm; n = 6).