| Co-Investigator(Kenkyū-buntansha) |
INAO Mie Saitama Medical School, Third Department of Internal Medicine, Tutor, 医学部, 助手 (70286037)
FUJIWARA Kenji Saitama Medical School, Third Department of Internal Medicine, Professor, 医学部, 教授 (80101088)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
TNF produced by activated macrophages in the hepatic sinusoids regulates the development of massive liver necrosis, and also acts as a cytokine to induce liver regeneration. It is well known that TNF binding to its receptor activates the caspase cascade resulting in apoptosis, whereas NFκB, an endogenous transcriptional factor activated by TNF, can inhibit this apoptosis. When mice received a small amount of TNF, liver injury is not induced, but massive liver necrosis following apoptosis occurs after TNF administration in mice pretreated with d-galactosamine (GalN), a transcription inhibitor. However, such massive liver necrosis is known to disappear in these mice given TNF 1 hour prior to GalN administration. In the present investigation, the mechanisms of this inhibitory action on apoptosis by TNF was studied in relation to inhibitor of apoptosis proteins (IAPs) which block apoptosis by binding to caspases. As IAPs, IAP-1, IAP-2, XIAP and survivin were used, and the expressions of these IAPs were evaluated in the liver by RT-PCR.When mice received TNF, IAP-1 and IAP-2 were expressed in the liver from 1 to 5 hours with the peak at 1 hour, but the expressions of XIAP and survivin showed the control levels until 8 hours. When mice were injected with GalN and 30 min later with TNF, the peak levels of IAP-1 and IAP-2 expressions showed the control levels, and apoptosis of hepatocytes developed with high serum ALT values, suggesting that the inhibitory action on apoptosis by TNF was produced via IAP-1 and IAP-2. It is concluded that IAP-1 and IAP-2 induced by TNF may regulate activated macrophages to work as inducing factors for massive liver necrosis or for liver regeneration.
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