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Cytokine production by heavy metals and its significance

重金属产生的细胞因子及其意义

基本信息

批准号：
15590112
负责人：
HIMENO Seiichiro
金额：
$ 2.18万
依托单位：
Tokushima Bunri University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590112/
关键词：
Cadmium Cytokine Manganese Hepatotoxicity Cadmium tolerance Mouse 金属化合物インターロイキン6 コバルト

项目摘要

Previously, we demonstrated that simultaneous administration of MnCl_2 with CdCl_2 resulted in significant reduction of acute Cd toxicity as determined by plasma GPT activity and testicular hemorrhage without affecting tissue accumulation of Cd. CoCl_2 also showed protective effects against acute Cd toxicity in mice. These findings were reconfirmed in metallothionein (MT) knockout mice, suggesting MT is not involved in Mn or Co protection against Cd toxicity. To explore the mechanism of protection against Cd toxicity, we examined the effects of co-administration of these metals with Cd on cytokine production since inflammatory cytokines are known to be involved in liver injury. We also determined plasma levels of acute phase protein, serum amyloid A (SAA), which is induced by cytokines in the liver when inflammation occurred. Among inflammatory cytokines examined, only IL-6 increased in the plasma after the administration of Mn and Co. The peaks of plasma IL-6 levels were observed at 6 h and 3 h by Mn and Co, respectively. Since MT production is, at least in part, involved in the protection against Cd toxicity by Mn, we focused on the effects of Cc on cytokine production. Cd administration itself also increased plasma levels of IL-6 and SAA. Co-administration of Co dose-dependently reduced the Cd-induced increases in plasma GPT activity and SAA levels. The reduced SAA levels in plasma reflected the reduced mRNA levels of SAA1 in the liver as measured by quantitative RT-PCR. However, co-administration of Co with Cd enhanced IL-6 production both at protein levels and mRNA levels. On the other hand, Cd-induced production of TNF-a was reduced by co-administration of Co. Therefore, it is suggested that Cc reduced the production of TNF-a caused by Cd, and consequently protected against hepatotoxicity and SAA production.

在此之前，我们证明了同时给药MnCl_2和CdCl_2可以显著降低急性Cd毒性（血浆GPT活性和睾丸出血），而不影响Cd的组织积累。CoCl_2对小鼠急性Cd毒性也有保护作用。这些发现在金属硫蛋白（MT）敲除小鼠中再次得到证实，表明MT不参与Mn或Co对Cd毒性的保护。为了探索抗Cd毒性的保护机制，我们研究了这些金属与Cd共同给药对细胞因子产生的影响，因为炎症细胞因子已知与肝损伤有关。我们还测定了急性期蛋白、血清淀粉样蛋白A （SAA）的血浆水平，SAA是在炎症发生时由肝脏细胞因子诱导的。在检测的炎症细胞因子中，只有IL-6在Mn和Co给药后血浆中升高。血浆IL-6水平分别在Mn和Co给药后6小时和3小时达到峰值。由于MT的产生至少在一定程度上参与了锰对Cd毒性的保护，因此我们重点研究了Cc对细胞因子产生的影响。Cd本身也增加了血浆中IL-6和SAA的水平。Co的剂量依赖性降低了cd诱导的血浆GPT活性和SAA水平的升高。定量RT-PCR检测血浆中SAA水平的降低反映了肝脏中SAA1 mRNA水平的降低。然而，Co与Cd的共给药在蛋白质水平和mRNA水平上都增加了IL-6的产生。另一方面，Cd诱导的TNF-a的产生减少了Co的共同给药。因此，这表明Cc减少了Cd引起的TNF-a的产生，从而保护了肝毒性和SAA的产生。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Overexpression of thioredoxin reductase 1 regulates NF-kB activation

硫氧还蛋白还原酶 1 的过度表达调节 NF-kB 激活

DOI：
发表时间：
2004
期刊：
J.Cell.Physiol. 198
影响因子：
0
作者：
Kondoh;M.et al.;Sakurai A. et al.
通讯作者：
Sakurai A. et al.

Induction of hepatic metallothionein by trivalent cerium: role of interleukin 6.

DOI：
10.1248/bpb.28.1859
发表时间：
2005-10
期刊：
Biological & pharmaceutical bulletin
影响因子：
2
作者：
Kazuo Kobayashi;Rumi Shida;T. Hasegawa;M. Satoh;Y. Seko;C. Tohyama;J. Kuroda;N. Shibata;N. Imura
通讯作者：
Kazuo Kobayashi;Rumi Shida;T. Hasegawa;M. Satoh;Y. Seko;C. Tohyama;J. Kuroda;N. Shibata;N. Imura

Induction of hepatic metallothionein synthesis by endoplasmic reticulum stress in mice