Shujiro Takamoto

Macrophage inflammatory protein-2 induced by TNF-α plays a pivotal role in concanavalin A-induced liver injury in mice

Abstract Background/Aims : Macrophage inflammatory protein-2 (MIP-2), one of the CXC chemokines, is involved in the recruitment of neutrophils in several tissue injuries. In this study, we investigated the role of MIP-2 in concanavalin A (Con A)-induced liver injury in mice. Methods : Liver injury was induced by intravenous injection of Con A (15 mg/kg) and plasma alanine aminotransferase (ALT), MIP-2 levels were determined and histological assessment of the liver was performed. Anti-mouse MIP-2 antibody was intravenously administered 30 min before Con A injection. Results : The plasma ALT level significantly elevated and reached a maximum at 8 h after Con A injection. The plasma MIP-2 level was also elevated and reached a peak value at 2 h after Con A injection. The elevated ALT level by Con A injection was significantly inhibited by the MIP-2 antibody. The elevated plasma MIP-2 level after Con A injection was significantly reduced by the tumor necrosis factor alpha (TNF- α ) antibody, and MIP-2 was induced in plasma after recombinant TNF- α injection. Hepatic necrosis and infiltration of neutrophils were observed after Con A injection, and these histological changes were attenuated by the MIP-2 antibody. Conclusions : These findings suggest that Con A induces TNF- α release, and this TNF- α stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

Antithrombin III prevents concanavalin A-induced liver injury through inhibition of macrophage inflammatory protein-2 release and production of prostacyclin in mice

BACKGROUND/AIMS Recently, we have reported that macrophage inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin A (Con A)-induced liver injury. In this study, we investigated the effect of antithrombin III (AT-III) on liver damage, and production of MIP-2 and prostacyclin in this model. METHODS Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1alpha (6k-PG-F1alpha), stable metabolite of prostaglandin I(2) (prostacyclin), were determined. RESULTS The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1alpha at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment. CONCLUSIONS These findings suggest that AT-III prevents Con A-induced liver injury through an inhibition of MIP-2 release and a production of prostacyclin.

Gender-related differences in concanavalin A-induced liver injury and cytokine production in mice.

BACKGROUND/AIM: Concanavalin A (Con A) activates T cells and causes T cell-mediated liver injury in mice. Since autoimmune diseases predominantly occur in women, female is considered to have enhanced immune responses and T cell functions. We investigated the presence of gender-related differences on Con A-induced liver injury and cytokine production in mice. METHODS: Male and female BALB/c mice were given Con A (15mg/kg) intravenously at 7 weeks of age. Plasma alanine aminotransferase (ALT), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin (IL)-4 and IL-10 levels were determined 0, 2, 4, 6, 8 and 24h after Con A administration. To investigate the effects of sex hormones on liver injury and cytokine production, female and male mice were castrated at 3 weeks of age and were administered Con A 4 weeks after the operation. RESULTS: Plasma ALT level of females was significantly higher at 8 and 24h after Con A administration than those of males. Plasma levels of TNF-alpha and IFN-gamma at 2, 4, 6 and 8h, IL-4 at 2h, but not IL-10, after Con A administration were significantly elevated in females than those of males. Furthermore, the elevated plasma ALT, TNF-alpha and IFN-gamma levels decreased significantly by an ovariectomy. In contrast, those markers were exacerbated by an orchiectomy compared with sham operation. CONCLUSION: These findings indicate that Con A induces more severe liver injury in female mice than in male mice, and suggest that the effect of sex hormones on cytokine production may play a role in gender-related difference on Con A-induced liver injury.

Effect of ursodeoxycholic acid on autoimmune-associated chronic hepatitis C

Background: Hypergammaglobulinaemia and various auto‐antibodies which are commonly seen in autoimmune hepatitis are also found in patients with chronic hepatitis C. We recently reported that ursodeoxycholic acid (UDCA) improved liver function tests and immunoserological markers in patients with type I autoimmune hepatitis. The aim of this study was to prospectively evaluate the efficacy of UDCA on autoimmune‐associated chronic hepatitis C.