ROLE OF PROINFLAMMATORY CYTOKINES IN ACETAMINOPHEN HEPATOTOXICITY
ROLE OF PROINFLAMMATORY CYTOKINES IN ACETAMINOPHEN HEPATOTOXICITY
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DOI：
10.1006/taap.1995.1125
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发表时间：
1995-07-01
影响因子：
3.8
通讯作者：
LUSTER, MI
中科院分区：
文献类型：
--
作者：
BLAZKA, ME;WILMER, JL;LUSTER, MI
对乙酰氨基酚（APAP）中毒已被证明激活枯否细胞。枯否细胞活化也与促炎细胞因子的释放相关，其可诱导多种病理生理反应。这些研究检查了促炎细胞因子是否响应于肝毒性剂量的APAP而产生，如果是，则它们在观察到的病理反应中发挥的作用。雌性B6 C3 F1小鼠在存在和不存在抗肿瘤坏死因子-α（TNF-α）、白细胞介素-1-α（IL-1 α）和IL-1受体拮抗剂（IL-1 ra）抗体的情况下接受500 mg APAP/kg。测定血清TNF-α、IL-1 α和肝脏相关酶水平。此外，通过逆转录-聚合酶链反应（RT-PCR）检查了处理小鼠肝脏中IL-1 α、IL-6和TNF-α的mRNA转录水平。施用APAP导致体温立即降低以及IL-1 α和TNF-α的血清水平升高，分别在12和16小时达到峰值。通过注射抗TNF-α或IL-1 α的抗体部分阻断体温的降低。此外，TNF-α的中和延迟了血清IL-1 α和肝酶水平的增加。相反，IL-1 ra抗血清预处理加剧了APAP对体温的影响，并增加了肝酶的释放。这些数据表明，TNF-α和IL-1 α响应于APAP中毒而释放，并且是APAP诱导的肝毒性的某些病理表现的原因。(C)出版社：Academic Press
Acetaminophen (APAP) intoxication has been shown to activate Kupffer cells. Kupffer cell activation is also associated with the release of proinflammatory cytokines which can induce a variety of pathophysiological responses. These studies examined whether proinflammatory cytokines are produced in response to a hepatotoxic dose of APAP, and if so, the role they play in the observed pathological response. Female B6C3F1 mice received 500 mg APAP/kg in the presence and absence of antibodies against tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha (IL-1 alpha), and IL-1 receptor antagonist (IL-1ra). Serum TNF-alpha, IL-1 alpha, and liver-associated enzyme levels were measured. In addition, the levels of mRNA transcripts for IL-1 alpha, IL-6, and TNF-alpha from livers of treated mice were examined by reverse transcription-polymerase chain reaction (RT-PCR). Administration of APAP resulted in an immediate reduction in body temperature as well as elevated serum levels of IL-1 alpha and TNF-alpha that reached a peak at 12 and 16 hr, respectively. The reduction in body temperature was partially blocked by injection of antibodies against TNF-alpha: or IL-1 alpha. Furthermore, neutralization of TNF-alpha delayed the increase in serum IL-1 alpha and liver enzyme levels. In contrast, pretreatment with IL-1ra antisera exacerbated the effect of APAP on body temperature and increased the release of liver enzymes. These data suggest that TNF-alpha and IL-1 alpha are released in response to APAP intoxication and are responsible for certain pathological manifestations of APAP-induced hepatotoxicity. (C) 1995 Academic Press, Inc.