Cytokine production by heavy metals and its significance

以前，我们证明，同时给予氯化锰CdCl_2导致显着减少急性镉毒性所确定的血浆谷丙转氨酶活性和睾丸出血，而不影响镉的组织积累。CoCl_2对小鼠急性镉中毒也有保护作用。这些发现在金属硫蛋白（MT）基因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。为了探索镉毒性的保护机制，我们研究了这些金属与镉共同管理对细胞因子产生的影响，因为已知炎症细胞因子参与肝损伤。我们还测定了急性时相蛋白血清淀粉样蛋白A（SAA）的血浆水平，当炎症发生时，SAA由肝脏中的细胞因子诱导。在检查的炎性细胞因子中，只有IL-6在血浆中增加后，管理的Mn和Co。血浆IL-6水平的峰值分别在6 h和3 h观察到Mn和Co。由于MT的生产，至少在部分，参与对镉毒性锰的保护，我们专注于CC对细胞因子的产生的影响。镉管理本身也增加了IL-6和SAA的血浆水平。共同管理的钴剂量依赖性地减少镉诱导的血浆GPT活性和SAA水平的增加。血浆中SAA水平的降低反映了肝脏中SAA 1 mRNA水平的降低，如通过定量RT-PCR测量的。然而，共同管理的钴镉增强IL-6的生产在蛋白水平和mRNA水平。另一方面，镉诱导的TNF-α的产生减少了共同管理的Co。因此，这表明，Cc减少了由镉引起的TNF-α的产生，从而防止肝毒性和SAA的生产。

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.