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Vitamin A and liver fibrosis
WS4-D-1-09 VITAMIN A AND LIVER FIBRO6IS M . O k u n o I , H.Morlwakl I , S.KoJi~a = , Y.Muto t , 1)First Dept Int Meal, Gifu Unlv Sch Med, Gifu, Japan Science Center, Institute for Physical Sciences, Tsukuba,
2) Tsukuba Japan
Li fe
A paradox has been reported regarding the effect of retinoids on liver fibrosis. Here, we report a conflicting effect of a retlnold analog in rat liver fibrosis models and its m e c h a n i s m empolylng cell culture systems. A retinolc acld annleg delayed the progress of liver parenchymal necros is in a liver fibrosis model induced by CC14, thereby inhibiting also the fibrosis. In contrast, the retlnold accelerated liver fibrosis in another liver fibrosis model induced by porcine serum which produces no parenchymal d~mage. The retlnold seemed to act directly on n o n parenchymal liver cells in the latter model to produce extrecellular matrices (ECM) since llver levels of both pro- a 2 (I) collagen BRNA and transforming growth factor (TGF)- ~ were ~ by the retlnold treatment. Hence, we next examined the effect of retlnolds on mesenchymal cells to elucidated the mechanism, Mploylng cell culture systems of rat stellate cells, mouse 3T3 L1 prendlpocytes and human TIG7 flbrobrasts. Retlnoids, especially all-trans (atRA) and 9-cls retinolc acld (9cRA), enhanced both BRNA and peptlde levels of proG 2 (I) collagen end tissue inhibitor of m e t a l l o p r o t e l n a s e (TIMP)-I while retlnolds reduced type I collagenase activities in these cultures, which were consistent with the observation in porcine serum-treated rats. These effects seemed to be mediated by TGF- ~ since both RA' s enhanced the release and activation of latent TGF- ~ in a dose-dependant manner and the retlnold effects on ECM production was blocked by a n t i - T G F - ~ antibody. Plasmin, which is also activated by retinolc acld-treatment, s ~ to participate, in part, in the release and activation of TGF- ~ . However the mechanism of the action of retlnolds on TGF- ~ remains to be clarified. These observations suggest that retlnolds, especially retinoic acid, enhance the production while reduce the degradation of ECM in the liver through the release and activation of TGF- ~ , acting directly on stellate cells.
WS4-D-I-10 FAS-FAS LIGAND INTERACTIONS UNDERLIE THE PATHOGENESIS OF ENDOTOXIN-iNDUCED LIVER INJURY H. Tsutsui 1, K. Takahashi2 K. Matsui 3, K. Nakanishi 4, K. Higashino 3, M. Inoue5 1 Toneyama Inst. for Tuberculosis Research and 5 Dept. of Biochemistry, Osaka City Univ. Medical School, 2 Osaka Prefectural College of Health Science, and Depts. of 3Internal Medicine III and 4Immunology and Medical Zoology, Hyogo College of Medicine. When a small dose of lipopolysaccharide (LPS) was injected into the mice that had been sensitized with heat-killed
Propionibacterium acnes (P. acnes) 7 days before, more than 50 % of mice died of endotoxin shock. The survived mice suffered from multiple organ failure, such as severe liver injury preceded by DNA fragmentation, and developed into severe immune depression. Intedeukin 10 (IL-10), a pleiopotent cytokine, has been reported to inhibit various functions of macrophages such as inflammatory cytokine production, expression of costimulatory factor, B7 and antigen presenting activity via MHC molecules, and to suppress inflammatory CD4 + T cell functions. To investigate whether the early lethal shock and the late liver injury were based on the same pathogenesis, the effect of IL-10 was tested on both events. IL-10 inhibited the lethal endotoxin shock without affecting the liver injury. IL-10 completely suppressed the elevation of serum inflammatory cytokines, such as interferon 7 (IFN-y)which is a potent lymphokine mainly produced by inflammatory CD4 + T cells (Thl) and tumor necrosis factor ¢xproduced by activated macrophages. IL-10, however, did not affect the functions of Kupffer cells and the infiltrated macrophages in the liver. By contrast, Ipr/fpr mice having functional mutation of the gene encoding Fas molecule died of endotoxin shock without showing any sign of liver injury, suggesting that Fas-Fas ligand system might be involved in this endotoxin-induced liver injury. In fact, after the sequential administration of P. acnes and LPS, Fas ligand was induced in the liver of both wild type and Ipr,qpr mice. Furthermore, the pretreatment with neutralyzing anti.IFN-y totally prevented the wild type mice from both endotoxin-inducod lethal shock and liver injury. These data suggested that the endotoxin shock and the liver failure might be induced by the different pathways triggered by the common key cytokine, IFN-y, and that the apoptotic cell death in the liver might be triggered by Fas-Fas ligand interaction. Identification of cell type(s) that expresses Fas ligand in the liver is under our current investigation.
260
2) Tsukuba Japan
Li fe
A paradox has been reported regarding the effect of retinoids on liver fibrosis. Here, we report a conflicting effect of a retlnold analog in rat liver fibrosis models and its m e c h a n i s m empolylng cell culture systems. A retinolc acld annleg delayed the progress of liver parenchymal necros is in a liver fibrosis model induced by CC14, thereby inhibiting also the fibrosis. In contrast, the retlnold accelerated liver fibrosis in another liver fibrosis model induced by porcine serum which produces no parenchymal d~mage. The retlnold seemed to act directly on n o n parenchymal liver cells in the latter model to produce extrecellular matrices (ECM) since llver levels of both pro- a 2 (I) collagen BRNA and transforming growth factor (TGF)- ~ were ~ by the retlnold treatment. Hence, we next examined the effect of retlnolds on mesenchymal cells to elucidated the mechanism, Mploylng cell culture systems of rat stellate cells, mouse 3T3 L1 prendlpocytes and human TIG7 flbrobrasts. Retlnoids, especially all-trans (atRA) and 9-cls retinolc acld (9cRA), enhanced both BRNA and peptlde levels of proG 2 (I) collagen end tissue inhibitor of m e t a l l o p r o t e l n a s e (TIMP)-I while retlnolds reduced type I collagenase activities in these cultures, which were consistent with the observation in porcine serum-treated rats. These effects seemed to be mediated by TGF- ~ since both RA' s enhanced the release and activation of latent TGF- ~ in a dose-dependant manner and the retlnold effects on ECM production was blocked by a n t i - T G F - ~ antibody. Plasmin, which is also activated by retinolc acld-treatment, s ~ to participate, in part, in the release and activation of TGF- ~ . However the mechanism of the action of retlnolds on TGF- ~ remains to be clarified. These observations suggest that retlnolds, especially retinoic acid, enhance the production while reduce the degradation of ECM in the liver through the release and activation of TGF- ~ , acting directly on stellate cells.
WS4-D-I-10 FAS-FAS LIGAND INTERACTIONS UNDERLIE THE PATHOGENESIS OF ENDOTOXIN-iNDUCED LIVER INJURY H. Tsutsui 1, K. Takahashi2 K. Matsui 3, K. Nakanishi 4, K. Higashino 3, M. Inoue5 1 Toneyama Inst. for Tuberculosis Research and 5 Dept. of Biochemistry, Osaka City Univ. Medical School, 2 Osaka Prefectural College of Health Science, and Depts. of 3Internal Medicine III and 4Immunology and Medical Zoology, Hyogo College of Medicine. When a small dose of lipopolysaccharide (LPS) was injected into the mice that had been sensitized with heat-killed
Propionibacterium acnes (P. acnes) 7 days before, more than 50 % of mice died of endotoxin shock. The survived mice suffered from multiple organ failure, such as severe liver injury preceded by DNA fragmentation, and developed into severe immune depression. Intedeukin 10 (IL-10), a pleiopotent cytokine, has been reported to inhibit various functions of macrophages such as inflammatory cytokine production, expression of costimulatory factor, B7 and antigen presenting activity via MHC molecules, and to suppress inflammatory CD4 + T cell functions. To investigate whether the early lethal shock and the late liver injury were based on the same pathogenesis, the effect of IL-10 was tested on both events. IL-10 inhibited the lethal endotoxin shock without affecting the liver injury. IL-10 completely suppressed the elevation of serum inflammatory cytokines, such as interferon 7 (IFN-y)which is a potent lymphokine mainly produced by inflammatory CD4 + T cells (Thl) and tumor necrosis factor ¢xproduced by activated macrophages. IL-10, however, did not affect the functions of Kupffer cells and the infiltrated macrophages in the liver. By contrast, Ipr/fpr mice having functional mutation of the gene encoding Fas molecule died of endotoxin shock without showing any sign of liver injury, suggesting that Fas-Fas ligand system might be involved in this endotoxin-induced liver injury. In fact, after the sequential administration of P. acnes and LPS, Fas ligand was induced in the liver of both wild type and Ipr,qpr mice. Furthermore, the pretreatment with neutralyzing anti.IFN-y totally prevented the wild type mice from both endotoxin-inducod lethal shock and liver injury. These data suggested that the endotoxin shock and the liver failure might be induced by the different pathways triggered by the common key cytokine, IFN-y, and that the apoptotic cell death in the liver might be triggered by Fas-Fas ligand interaction. Identification of cell type(s) that expresses Fas ligand in the liver is under our current investigation.
260