Enhancement by galactosamine of lipopolysaccharide(LPS)-induced tumour necrosis factor production and lethality: its suppression by LPS pretreatment
Enhancement by galactosamine of lipopolysaccharide(LPS)-induced tumour necrosis factor production and lethality: its suppression by LPS pretreatment
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DOI：
10.1038/sj.bjp.0702747
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发表时间：
1999-09-01
影响因子：
7.3
通讯作者：
Kumagai, K
中科院分区：
文献类型：
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作者：
Endo, Y;Shibazaki, M;Kumagai, K
1 D-半乳糖胺 (GalN) 主要消耗肝脏中的 UTP，导致肝细胞中 RNA 合成减少。将 GalN 和脂多糖 (LPS) 注射到小鼠体内会产生暴发性肝炎，并伴有严重的肝充血，导致小鼠迅速死亡。尽管根本机制尚不清楚，但 GalN 增强了对肿瘤坏死因子 (TNF) 的敏感性。在注射 LPS 本身或白细胞介素 1 (IL-1) 之前给予尿苷（UTP 的前体）可降低 GalN + LPS 的致死率。本研究重点关注这些药物对 TNF 产生的影响。2 给小鼠腹腔注射 GalN + LPS 显着升高血清 TNF。尽管单独使用大剂量的LPS也会大大升高血清TNF，但LPS本身既不会引起肝充血，也不会导致快速死亡。施用巨噬细胞消耗剂、用二氯亚甲基二膦酸盐封装的脂质体，减少了GalN+LPS诱导的TNF产生和死亡率。3当注射GalN+LP'S后0.5小时注射尿苷时，减少了TNF的产生。预先注射 LPS（而非 IL-1）也减少了 TNF 的产生。4 来自注射 LPS 的小鼠的血清减少了 GalN + LPS 诱导的 TNF 产生，但在降低致死率方面效果较差。热处理消除了其减少 TNF 产生的能力。5 我们假设肝细胞响应 LPS 产生抑制巨噬细胞产生 TNF 的因子。这种肝细胞来源的 TNF 下调因子 (TNF-DRh) 的产生可能是：(i) 被 GalN 抑制，导致巨噬细胞过度产生 TNF；(ii) 被 LPS 预处理刺激（并被尿苷恢复），导致 TNF 产生减少。
1 D-Galactosamine (GalN) depletes UTP primarily in the liver, resulting in decreased RNA synthesis in hepatocytes. Go-injection of GalN and lipopolysaccharide (LPS) into mice produces fulminant hepatitis with severe hepatic congestion, resulting in rapid death. Although the underlying mechanism is uncertain, GalN enhances the sensitivity to tumour necrosis factor (TNF). Administration of uridine (a precursor of UTP) prior injection of either LPS itself or interleukin-1 (IL-1) reduces the lethality of GalN + LPS. The present study focused on the effects of these agents on TNF production.2 Intraperitoneal injection of GalN + LPS into mice greatly elevated serum TNF. Although large doses of LPS alone also greatly elevated serum :TNF, LPS itself induced neither hepatic congestion nor rapid death. Administration of a macrophage depletor, liposomes encapsulated with dichloromethylene bisphosphonate, reduced both the TNF production and mortality induced by GalN + LPS.3 Uridine, when injected 0.5 h after the injection of GalN + LP'S, reduced the production of TNF. Prior injection of LPS, but not of IL-1, also reduced this TNF production.4 Serum from LPS-injected mice reduced the TNF production induced by GalN + LPS, but it was less effective at reducing the lethality. Its ability to reduce TNF production was abolished by heat-treatment.5 We hypothesize that a factor inhibiting TNF production by macrophages is produced by hepatocytes in response to LPS. Possibly, production of this hepatocyte-derived TNF-down-regulator (TNF-DRh) may be: (i) inhibited by GalN, causing over-production of TNF by macrophages and (ii) stimulated by LPS-pretreatment (and restored by uridine), causing reduced TNF production.