Takashi Yamanaka

Involvement of tumor necrosis factor-α in the pathogenesis of activated macrophage-mediated hepatitis in mice

The possible involvement of tumor necrosis factor-alpha in the pathogenesis of an experimentally induced hepatitis was investigated. Balb/c mice were primed with Propionibacterium acnes to induce the infiltration of mononuclear cells into the liver. Immunohistochemical study showed that most of the accumulated mononuclear cells at 7 days were Mac-2 positive, suggesting that they were activated macrophages. An injection of lipopolysaccharide resulted in massive hepatic necrosis and high mortality in the mice within 24 hours. Plasma tumor necrosis factor-alpha activity initially rose sharply and then declined over 3 hours. The increase in plasma aminotransferase activity correlated well with the elevation of plasma tumor necrosis factor-alpha activity. Pretreatment with dexamethasone or 16,16-dimethyl-prostaglandin E2 attenuated not only the elevation of plasma tumor necrosis factor-alpha activity but also the increase in plasma aminotransferase activity and improved the survival rate. Passive immunization against tumor necrosis factor-alpha showed protective effects. These findings suggest that tumor necrosis factor-alpha released from activated macrophages may play a crucial role in the pathogenesis of this murine hepatitis.

Effects of geranygeranylacetone on gastrointestinal secretion in rats

The effects of geranylgeranylacetone (GGA), a new acyclic polyisoprenoid with a novel antiulcer action on gastrointestinal secretion were studied in rats. Intraduodenal administration of GGA (1-30 mg/kg) dose-relatedly reduced the gastric acid secretion caused by pentagastrin, histamine or insulin. On the other hand, GGA (3-30 mg/kg i.d.) dose-relatedly increased pancreatic secretion but did not affect biliary secretion. The above-mentioned findings seem consistent with the further findings that GGA depressed a plasma gastrin level enhanced by insulin while in increased the basal level of plasma secretin. These pharmacological features found in the present studies may partially, at least, account for the mechanism of GGA antiulcer action.

Suppressive effects of E3330, a novel quinone derivative, on tumor necrosis factor-α generation from monocytes and macrophages

E3330 {(2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonly-2-propenoic acid}, a novel synthesized hepatoprotective compound, has suppressive effects on tumor necrosis factor-α (TNF-α) generation from monocytes/macrophagesin vitro. E3330 (1–100 μM) reduced lipopolysaccharide (LPS, 10 mg/ml or 1μg/ml)-induced TNF-α generation from rat resident andPropionibacterium acnes (P. acnes)-elicited peritoneal macrophages, rat and human monocytes, rat Kupffer cells, and splenic mononuclear cells in a concentration-dependent manner. E3330 also (1–100 μM) suppressed TNF-α generation stimulated with egg-albumin immune complex in ratP. acnes-elicited peritoneal macrophages. Northern blot analysis showed that LPS-induced expression of TNF-α messenger RNA (mRNA) in human blood monocytes was suppressed by E3330. These findings indicate that E3330 has a suppressive effect on TNF-α generation from monocytes/macrophages, regardless of origin or species, and this effect is based in part on the suppression of TNF-α mRNA expression.

EICOSANOID PROFILE AND EVIDENCE FOR ENDOTOXIN TOLERANCE IN CHRONIC ETHANOL-FED RATS

The present study evaluated the role of endotoxin, prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and thromboxane B2 in alcoholic liver injury. Animals (4-5 per group per time period) were fed ethanol and either saturated fat (SE group) or corn oil (CE group) and sacrificed at various time intervals: 1, 2, and 4 weeks. Non parenchymal cells (NPC) were isolated and the spontaneous and LPS-stimulated production of eicosanoids was evaluated. In addition, severity of pathology, plasma levels of endotoxin, TXB2, LTB4 and PGE2 were compared in the two groups. The severity of fatty, liver, necrosis and inflammation was significantly greater in the CE group compared to the SE group after 1 month. Plasma endotoxin levels were significantly higher in the CE group vs. SE group at all time periods studied. PGE2 levels in NPCS and plasma were in general higher in the SE group. LTB4 levels in NPCS declined with time in the SE group; in contrast the levels rose in the CE group. There was no difference in LTB4 levels in plasma between the two groups. TXB2 levels in plasma and NPCS were significantly higher in the CE group at all times. The pattern of LPS-stimulated eicosanoid production by NPC in the two groups (SE and CE) suggested the development of endotoxin tolerance in the CE group. However, an additional modulatory effect of ethanol was also suggested by our findings.

Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice

Oral pretreatment with E3330, a novel quinone derivative, attenuated liver injury induced with tumor necrosis factor-alpha in galactosamine-sensitized mice. Tumor necrosis factor-alpha is known to induce inflammatory mediators such as leukotrienes and prostanoids. An in vitro study showed that E3330 inhibited the generation of leukotriene B4 and thromboxane B2, but enhanced prostaglandin E2 generation from rat peritoneal exudate cells stimulated with the Ca(2+)-ionophore, A23187. These findings suggest that the protective effect of E3330 on galactosamine/tumor necrosis factor-alpha hepatitis is due at least in part to its inhibition of the generation of leukotrienes. The inhibition of thromboxane B2 generation or the enhancement of prostaglandin E2 generation by E3330 may also contribute to its hepatoprotective effect.

Interleukin-Lα Enhances Hepatotoxicity of Tumor Necrosis Factor-α in Galactosamine-Sensitized Mice

AbstractThe possible involvement of interleukin-lα (IL-lα) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. the injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1α antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-α (TNF) antiserum significantly protected mice from liver injury. the use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-lα could not substitute for LPS. However, recombinant murine IL-lα enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-lα acts synergistically with TNF ...

Ethanol-induced suppression of interleukin 1-like activity : reversal by a quinone derivative

Chronic ethanol intake impairs several parameters of immune function. Since there is evidence that cytokine production by immune cells may contribute to the immunosuppressive effect of ethanol, we examined interleukin 1 (IL1) production by liver non-parenchymal cells (NPC) in ethanol-fed rats. Male Wistar rats (225-250 g) were fed by continuous intragastric infusion. The source of fat was either saturated fat or polyunsaturated fat. In addition, the effect of a quinone compound on IL1 production was assessed. Animals were fed for various periods: 1 week, 2 weeks, 1 month and 2 months. NPC were isolated and stimulated by lipopolysaccharide. IL1 production by NPC and the ratio of stimulated to unstimulated (S:U) IL1 production were evaluated in the different groups and related to the presence of liver injury. As expected, animals fed corn oil and ethanol (CO+E) developed pathologic liver injury, whereas animals fed saturated fat and ethanol (SF+E) had no liver injury. A progressive decrease in the S:U IL1 ratio was seen in the CO+E group over the 8-week period. The ratio in the SF+E group was higher. The quinone compound reversed the suppressive effect of ethanol on IL1 production. In summary, ethanol-induced suppression of IL1 production was modulated by diet and the presence of liver injury. This suppression of IL1 production was reversed by a quinone compound; the exact mechanism for the reversal of this inhibition is unknown.