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Thesis
Tumor Necrosis Factor-αのマウス肝細胞アポトーシス抑制作用におけるInhibitor of Apoptosis Proteins の関与

菅原　通子
埼玉医科大学内科学消化器・肝臓内科部門

共同研究者：名越　澄子（埼玉医科大学内科学消化器・肝臓内科部門），善本　隆之（東京医科大学内科学難病治療研究センター），持田　智（埼玉医科大学内科学消化器・肝臓内科部門），藤原　研司（独立行政法人労働者健康福祉機構横浜労災病院）

医学博士　甲第978号　平成17年3月25日 （埼玉医科大学）

【Background and Aims】 Tumor Necrosis Factor-α (TNF-α) 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-α binding to its receptor activates caspase cascade resulting in apoptosis, whereas this apoptosis is inhibited by NFκB, an endogenous transcriptional factor activated by TNF-α. Moreover, inhibitor of apoptosis proteins (IAPs) are accelerated in the transcription by NFκB, and can bind to the caspases to inactivate caspase cascade. In mice given a small amount of TNF-α, liver injury is not induced, but massive liver necrosis occurs following hepatocyte apoptosis after TNF-α administration in mice pretreated with d-galactosamine (GalN), a transcription inhibitor. In the present investigation, the relation of this inhibitory action of TNF-α on hepatocyte apoptosis to IAPs was studied using this model and other mouse models. 【Methods and Results】With the following models, the hepatic expressions of IAPs were evaluated as IAP-1, IAP-2, XIAP and survivin mRNAs by RT-PCR. Hepatocyte apoptosis was determined by TUNEL method. 1) When mice received TNF-α, IAP-1 and IAP-2 were up-regulated in the liver from 1 to 5 hr with their peaks at 1 hr, but the expressions of XIAP and survivin were at the control levels until 8 hr. However, pretreatment with GalN before 30 min showed apoptosis in half of hepatocytes at 8 hr after TNF-α administration, with IAP-1 and IAP-2 expressions at the control levels at 1 hr. 2) Serum TNF-α concentration was increased later than 1 hr after endotoxin dosing in mice pretreated with P. acnes, but hepatocyte apoptosis was absent until 8 hr. Hepatic expressions of IAP-1 and IAP-2 were increased forming their peaks at 2 hr, but hepatic expressions of XIAP and survivin were unchanged until 8 hr. 3) IAP-1, IAP-2 and XIAP expressions were not changed from 10 min to 5 days after 70％ liver resection, whereas survivin expression was increased at 36 and 48 hr after the operation. 【Conclusions】The inhibitory action of TNF-α on hepatocyte apoptosis may be produced via IAP-1 and IAP-2. However, hepatocytes during liver regeneration may be protected from apoptosis through different mechanisms, especially by action of survivin.
Keywords: apoptosis . hepatocyte. TNF-α. IAPs. NFκB.