Induction of metallothionein by manganese is completely dependent on interleukin-6 production
Induction of metallothionein by manganese is completely dependent on interleukin-6 production
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DOI：
10.1124/jpet.106.112912
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Himeno, Seiichiro
中科院分区：
文献类型：
--
作者：
Kobayashi, Kazuo;Kuroda, Junji;Himeno, Seiichiro
金属硫蛋白（MT）是一种富含半胱氨酸的蛋白质，可与镉和锌等重金属结合并被其诱导。然而，其他金属诱导MT的确切机制尚不清楚。在本研究中，我们研究了锰诱导MT的机制，重点是细胞因子的产生。给小鼠施用MnCl2导致肝脏中MT的剂量依赖，锰的积累很少。肝细胞质中金属的形态分析表明，与诱导的MT结合的主要金属是锌。MnCl2引起肝脏中白细胞介素-6 (IL-6) mRNA水平的升高以及血清IL-6水平的升高，但没有引起其他炎症细胞因子水平的升高。随后，血清中IL-6诱导的急性期蛋白血清淀粉样蛋白A （SAA）水平升高，并在24 h达到峰值。然而，血清丙氨酸转氨酶活性未见升高，表明锰在不引起肝损伤的情况下促进了IL-6和SAA的生成。在IL-6的作用下，锌转运蛋白ZIP14在肝脏中的表达增强，这可能有助于肝脏锌- mt的合成。在il -6缺失的小鼠中，MnCl2对肝脏MT的诱导被完全抑制到对照水平。这些结果表明，锰是一种独特的金属，完全依赖于IL-6的产生而不伴随肝损伤诱导肝脏MT的合成。
Metallothionein (MT) is a cysteine-rich protein that binds to and is inducible by heavy metals such as cadmium and zinc. However, the precise mechanism of MT induction by other metals remains unclear. In the present study, we investigated the mechanism of MT induction by manganese, focusing on the involvement of cytokine production. Administration of MnCl2 to mice resulted in the induction of MT dose-dependently in the liver with little accumulation of manganese. Speciation analysis of metals in the liver cytosol showed that the major metal bound to the induced MT was zinc. Administration of MnCl2 caused an increase in mRNA levels of interleukin-6 (IL-6) in the liver as well as an increase in serum levels of IL-6 but not those of other inflammatory cytokines. Subsequently, serum levels of serum amyloid A (SAA), an acute-phase protein induced by IL- 6, increased with a peak at 24 h. However, no increase in serum alanine aminotransferase activity was observed, suggesting that manganese enhanced the production of IL-6 and SAA without causing liver injury. In response to IL-6, the expression of a zinc transporter, ZIP14, was enhanced in the liver, possibly contributing to the synthesis of hepatic zinc-MT. In IL-6-null mice, the induction of hepatic MT by treatment with MnCl2 was completely suppressed to the control level. These results suggest that manganese is a unique metal that induces the synthesis of hepatic MT completely depending on the production of IL-6 without accompanying liver injury.