Serum amyloid A-luciferase transgenic mice: Response to sepsis, acute arthritis, and contact hypersensitivity and the effects of proteasome inhibition
Serum amyloid A-luciferase transgenic mice: Response to sepsis, acute arthritis, and contact hypersensitivity and the effects of proteasome inhibition
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DOI：
10.4049/jimmunol.174.12.8125
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发表时间：
2005-06-15
影响因子：
4.4
通讯作者：
West, DB
中科院分区：
文献类型：
--
作者：
Zhang, N;Ahsan, MH;West, DB
急性期血清淀粉样蛋白 A (A-SAA) 是在炎症急性期以及慢性炎症性疾病发展过程中大量产生的多功能载脂蛋白。在这项研究中，我们提出了一种 Saa1-lue 转基因小鼠模型，其中可以通过使用非侵入性成像系统测量荧光素酶活性来监测 SAA1 基因表达。当用 LPS、TNF-α 或 IL-1β 攻击时，Saa1-luc 小鼠的体内成像显示，肝区荧光素酶活性诱导了 1000 至 3000 倍，并在治疗后 4-7 小时达到峰值。肝脏荧光素酶表达的诱导与肝脏中 SAA1 mRNA 的增加和血清 SAA1 浓度的显着升高一致。离体分析显示，LPS 或 TNF-α 处理后，许多组织中荧光素酶的诱导程度从几倍（脑）到 > 5000 倍（肝脏）不等。用蛋白酶体抑制剂硼替佐米预处理小鼠可显着抑制 LPS 诱导的 SAA1 表达。这些结果表明，蛋白酶体抑制可能通过 NF-kappa B 信号通路调节 SAA1 表达。在关节内给予酵母聚糖引发的急性关节炎的发展过程中，SAA1的表达在膝关节局部和肝脏中均被诱导，并且硼替佐米显着抑制这种诱导。 SAA1 表达的诱导也在局部应用恶唑酮诱导的接触超敏反应期间得到证实。这些结果表明，A-SAA 的局部和全身诱导均发生在炎症过程中，并且可能有助于与淀粉样蛋白沉积相关的慢性炎症性疾病的发病机制。
Acute phase serum amyloid A proteins (A-SAAs) are multifunctional apolipoproteins produced in large amounts during the acute phase of an inflammation and also during the development of chronic inflammatory diseases. In this study we present a Saa1-lue transgenic mouse model in which SAA1 gene expression can be monitored by measuring luciferase activity using a noninvasive imaging system. When challenged with LPS, TNF-alpha, or IL-1 beta, in vivo imaging of Saa1-luc mice showed a 1000- to 3000-fold induction of luciferase activity in the hepatic region that peaked 4-7 h after treatment. The induction of liver luciferase expression was consistent with an increase in SAA1 mRNA in the liver and a dramatic elevation of the serum SAA1 concentration. Ex vivo analyses revealed luciferase induction in many tissues, ranging from several-fold (brain) to > 5000-fold (liver) after LPS or TNF-a treatment. Pretreatment of mice with the proteasome inhibitor bortezomib significantly suppressed LPS-induced SAA1 expression. These results suggested that proteasome inhibition, perhaps through the NF-kappa B signaling pathway, may regulate SAA1 expression. During the development of acute arthritis triggered by intra-articular administration of zymosan, SAA1 expression was induced both locally at the knee joint and systemically in the liver, and the induction was significantly suppressed by bortezomib. Induction of SAA1 expression was also demonstrated during contact hypersensitivity induced by topical application of oxazolone. These results suggest that both local and systemic induction of A-SAA occur during inflammation and may contribute to the pathogenesis of chronic inflammatory diseases associated with amyloid deposition.