Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production

Abstract

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 MnCl 2 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 MnCl 2 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 MnCl 2 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.Metallothionein (MT) is a cysteine-rich low-molecularweight protein with a high affinity for heavy metals. Physiological roles of MT encompass a broad spectrum, including detoxification of heavy metals, scavenging of free radicals, regulation of cell growth, and maintenance of homeostasis of trace metals such as zinc and copper (Suzuki et al., 1993). The most prominent characteristic of MT is its inducibility not only by metals but also by various factors such as hormones, cytokines, organic chemicals, starvation, and physical stress (Kä gi, 1993). It is generally perceived that the expression of the MT gene in response to a metal load is regulated by metal-responsive transcription factor 1 (MTF-1) that binds to the metal-response elements of the promoter region of MT genes (Heuchel et al., 1994). The mechanisms underlying the activation of the MT gene through the interaction of MTF-1 and metal-response elements have been investigated extensively (Andrews, 2001;Otsuka, 2004), but the precise mechanism of MT induction by nonzinc metals, including cadmium has been poorly understood (Daniels et al., 2002;Wang et al., 2004).In addition to potent MT-inducing metals such as zinc, cadmium, copper, mercury, silver, and bismuth, other metals such as chromium, iron, cobalt, nickel, arsenic, and manganese can also induce MT but to the lesser levels (Fleet et al., 1990;Albores et al., 1992). These weak MT-inducing metals

Effects of feed supplementation with manganese from its different sources on performance and egg parameters of laying hens

“…The oxidative stability of yolk lipids was not significantly different during whole time of storage (40 days) in both groups of birds fed diets enriched with manganese from organic sources. One of the most important functions of Mn is related to its antioxidative effect mediated by Mn-superoxide dismutase, or by increasing the synthesis of metallothionein (Kobayashi et al, 2007), which can reduce oxidative damage caused by free radicals. The suppression of lipid oxidation in egg yolk from hens supplemented with organic Mn sources may be explained by this hypothesis.…”

Mechanisms of cadmium-induced chronotoxicity in mice

“…The hepatic cytosol fractions of Cd-injected mice were analyzed by HPLC-ICP/MS. The column (TSK gel G3000SW) used in this analysis can separate the two major MT isoforms (MT-1 and MT-2) in a single elution (Kobayashi et al, 2007). As shown in Fig.…”

“…Supernatants were assayed for reduced-form of GSH using GSSG/GSH Quantification Kit (Dojindo Laboratories, Kumamoto, Japan) according to the manufacture's instruction. The hepatic MT protein levels were determined by Hgbinding assay (Kobayashi et al, 2007). Mercury bound to MT was measured using a mercury analyzer RA-2A (Nippon Instruments, Tokyo, Japan).…”

Dichotomous Effects of Lead Acetate on the Expression of Metallothionein in the Liver and Kidney of Mice

“…Recently, we have demonstrated that interleukin-6 (IL-6) produced by various metal compounds such as Mn, cerium (Ce) and vanadium (V) plays an important role in the induction of MT in the liver. [6][7][8] However, little information is available concerning MT induction by Pb compounds. An early study in 1980s showed that intraperitoneal administration of Pb increased the protein amount of Zn-thionein in the liver of rats.…”