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TOXICOLOGY
Toxicology Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., Nagano, Japan (K.K., J.K., N.S.); Department of Environmental Biochemistry, Yamanashi Institute of Environmental Sciences, Yamanashi, Japan (T.H., Y.S.); Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Japan (M.S., C.T., H.T.); Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (N.I., K.S.); and Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan (H.F., S.H.)
Received for publication
August 23, 2006
Accepted
October 19, 2006.
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Abstract |
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). 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 (Kägi, 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 cannot bind to MT protein. It has been considered that MT induction by these metals is mediated by inflammation or stress responses, but the exact mechanisms have not yet been fully elucidated.
Several metals are known to induce inflammatory cytokines in animals. For instance, cadmium induces tumor necrosis factor (TNF)-
, interleukin (IL)-1
, IL-6, and interferon (IFN)-
(Kayama et al., 1995). TNF-, IL-1, IL-6, and IFN- are well known inducers of hepatic MT (De et al., 1990). IL-6 induces MT-I and MT-II in the brain also (Penkowa and Hidalgo, 2000). The involvement of a signal transducer and activator of transcription (STAT) in the expression of the MT gene in response to IL-6 stimulation has been postulated (Lee et al., 1999). Recently, we have demonstrated that trivalent cerium (Kobayashi et al., 2005) and pentavalent vanadium (Kobayashi et al., 2006) are rather potent MT inducers, and the production of IL-6 by these metals is, at least in part, involved in MT induction. However, quantitative analyses on the involvement of IL-6 in the induction of MT by other metals have not been examined.
An early study by Yoshikawa (1970) showed that pretreatment with manganese protected against the lethal toxicity of cadmium. Goering and Klaassen (1985) also reported the reduction of cadmium-induced liver damage by pretreatment with manganese and suggested that the protective action of manganese might be explained by MT induction. Several studies have shown manganese-induced MT synthesis in the liver of animals (Suzuki and Yoshikawa, 1976; Eaton et al., 1980; Waalkes and Klaassen, 1985). On the other hand, Bracken and Klaassen (1987) reported that manganese did not induce MT in primary cultured rat hepatocytes, suggesting that the manganese-induced hepatic MT synthesis is caused by an indirect mechanism. However, the mechanism of MT induction by manganese has not yet been elucidated.
In the present study, we investigated the mechanism of MT induction by manganese in mice and found that manganese has an ability to induce hepatic MT but does not bind to the induced MT. Determination of cytokine production and utilization of IL-6-null mice revealed that hepatic MT synthesis by manganese was completely dependent on IL-6 production. This is the first report demonstrating that the induction of MT by a metal compound is exclusively mediated by the production of IL-6.
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Materials and Methods |
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Treatment of Mice with MnCl2. Male ICR mice were treated s.c. with MnCl2 dissolved in saline at doses of 150, 300, 450, and 600 µmol/kg. Control mice were given saline. The animals were sacrificed at 24 h after MnCl2 treatment, and blood was collected under anesthesia. The serum was separated by centrifugation. The activity of alanine aminotransferase (ALT) and the concentration of blood urea nitrogen (BUN) were determined using an automatic analyzer (model 7150; Hitachi Co., Tokyo, Japan). The concentration of serum amyloid A (SAA) was determined using a Cytoscreen ELISA kit (BioSource International, Camarillo, CA). The liver and kidney tissues were stored frozen at –80°C until subsequent analyses of metal and MT concentrations. In a time course experiment, male ICR mice were sacrificed at 0, 1.5, 3, 6, 12, 24, and 48 h after treatment with MnCl2 (300 µmol/kg s.c.). Serum samples of animals were collected and used for analyses of TNF-, IL-1, IL-6, IFN-, and SAA. The liver was removed for the measurement of manganese. The serum concentrations of cytokines and SAA were measured using Cytoscreen ELISA kit (BioSource International). To determine dose-dependent changes of serum IL-6 concentrations by MnCl2 administration, male ICR mice were treated s.c. with MnCl2 at doses of 0, 50, 100, 150, 300, 450, and 600 µmol/kg. Animals were sacrificed at 6 h after treatment, and serum IL-6 concentration was determined. To obtain more direct evidence for the role of IL-6 in the induction of MT by manganese, male IL-6-null mice and wild-type mice were treated s.c. with MnCl2 at doses of 0, 150, and 300 µmol/kg. Animals were sacrificed 24 h after the treatment, and the serum concentration of SAA was determined. The liver was removed, and the concentration of MT was measured.
Determination of Metals and MT in Tissues. The liver and kidney samples were digested with nitric acid. The concentration of manganese in each sample was determined using an atomic absorption spectrophotometer (SPECTRAA 400; Varian, Inc., Palo Alto, CA). The concentration of MT was determined by a Hg2+-binding assay (Himeno et al., 2000) as modified from the original 203Hg-binding assay (Naganuma et al., 1987). Mercury bound to MT was measured by atomic absorption spectrophotometry using a mercury analyzer (RA-2A; Nippon Instruments, Tokyo, Japan) after digestion with nitric acid. The MT content was expressed as nanomoles of mercury bound.
Distribution Profiles of Metals in Liver Cytosol. The distribution profiles of metals in the soluble fraction of the liver of mice were analyzed using high-performance liquid chromatography (HPLC)/inductively coupled argon plasma-mass spectrometry (ICP-MS) as described by Suzuki (1991) with a modification. Portions of liver samples from three mice obtained 24 h after the treatment with MnCl2 (300 µmol/kg s.c.) were pooled and homogenized in 4 volumes of saline. The homogenate was centrifuged at 4°C for 1 h at 105,000g. The liver of mice obtained 24 h after the treatment with CdCl2 (10 µmol/kg s.c.) was prepared in the same manner as a positive control. An aliquot (40 µl) of the supernatant was applied to a TSK gel G3000SW column (7.5 x 600 mm with a 7.5 x 75 mm guard column; Tosoh, Tokyo, Japan). The loaded sample was eluted with 50 mM Tris-HCl (pH 8.6, containing 0.1% sodium azide) at a flow rate of 0.8 ml/min on an HPLC instrument (HP1100; Yokogawa Analytical Systems, Musashino, Japan). The eluate was monitored at 280 nm and introduced directly into the nebulizer capillary of an ICP-MS apparatus (HP4500; Yokogawa Analytical Systems). The distribution profiles of manganese, cadmium, zinc, and copper were determined at the mass numbers of 55, 111, 66, and 63, respectively.
Determination of mRNA Levels of IL-6 and ZIP14. Male ICR mice were sacrificed 0, 1, 3, 6, 12 and 24 h after the treatment with MnCl2 (300 µmol/kg s.c.). Total RNA was extracted from the liver and kidney tissues of mice using the guanidium thiocyanate-phenol-chloroform extraction method as described by Chomczynski and Sacchi (1987). A reverse transcription (RT) reaction was performed in a mixture containing 50 mM Tris-HCl, pH 8.3, 70 mM KCl, 3 mM MgCl2, 10 mM dithiothreitol, 1 mM concentrations each of dNTPs, 4 U of RNase inhibitor, 2 µg of total RNA, 0.5 µM oligo(dT)15 primer (Promega, Madison, WI), and 5 U of reverse transcriptase in a total volume of 20 µl. The reaction was carried out at 37°C for 1.5 h. The RT reaction mixture was used directly for PCR amplification. Quantitative real-time RT-PCR was performed using a TaqMan probe according to the procedure recommended by the manufacturer (Applied Biosystems, Foster City, CA). For cDNA synthesis, 450 ng of total RNA was used. The forward and reverse primers and TaqMan probes for IL-6, ZIP14, and glyceraldehyde-3-phosphate dehydrogenase were supplied by TaqMan Assay-on-Demand Products (Applied Biosystems). PCR amplifications were always performed using universal temperature cycles: 10 min at 94°C, followed by 35 to 45 two-temperature cycles (15 s at 94°C and 1 min at 60°C). Fluorescence of PCR products was detected using an ABI Prism 7300/7500 sequence detector system (Applied Biosystems).
Statistical Analysis. Statistical significance was determined by using one-way analysis of variance followed by a Bonferroni multiple comparison test. If the data were not normally distributed, we used the Kruskal-Wallis test (nonparametric analysis of variance) followed by Dunn's multiple comparison test. Differences between groups were considered significant at P < 0.05.
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Results |
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). As shown in Fig. 2, manganese was detected mainly in the high-molecular-weight fraction. On the other hand, two clear peaks of zinc (retention times 22.1 and 23.6 min) were detected in the liver cytosol of MnCl2-treated mice. These peaks corresponded to the two peaks of cadmium (retention times 22.0 and 23.5 min) in the liver cytosol of CdCl2-treated mice used as a positive control. These data indicate that the major metal bound to the MT induced by the administration of MnCl2 was zinc, not manganese.
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Changes in Biochemical Markers of Tissue Injury after MnCl2 Administration. To explore possible involvement of tissue injury caused by MnCl2 in MT induction, we determined biochemical markers for liver and kidney injury. However, no increase in the activity of ALT or the concentration of BUN was observed. On the other hand, the concentration of SAA, an acute-phase protein, increased markedly and dose-dependently 24 h after the treatment with MnCl2 (Fig. 3A). These data suggest that the administration of MnCl2 did not cause hepatic and renal injury but enhanced the serum levels of SAA.
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, IL-1, or IFN- were found after the MnCl2 administration (data not shown). The concentrations of SAA began to increase at 12 h after the MnCl2 administration and reached a peak level at 24 h (Fig. 4C). To examine the dose dependence of IL-6 production by MnCl2 administration, serum IL-6 concentration was measured at 6 h after the treatment with MnCl2 (0–600 µmol/kg). The serum IL-6 levels were increased dose-dependently by MnCl2 administration (Fig. 5).
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mRNA Levels of IL-6 and ZIP14. To confirm the expression of IL-6 gene in the liver, the mRNA levels of IL-6 in the livers of MnCl2-treated mice were evaluated by a real-time RT-PCR. As shown in Fig. 6A, the levels of IL-6 mRNA increased with a peak at 3 h after the MnCl2 administration. No increase in IL-6 mRNA was found in the kidney (data not shown). Recently, IL-6-induced up-regulation of ZIP14, a zinc transporter responsible for the incorporation of zinc from the serum to the tissue, was reported (Liuzzi et al., 2005). As shown in Fig. 6B, administration of MnCl2 markedly enhanced the mRNA levels of ZIP14. The maximal levels were observed 6 to 12 h after MnCl2 administration, suggesting that this increase is caused by the expression of the IL-6 gene in the liver. However, no apparent increases in ZIP14 mRNA levels were observed in the kidney (data not shown). Thus, it seems likely that the administration of MnCl2 induced the expression of IL-6 in the liver, and then the IL-6 induced the expression of both MT and ZIP14 genes, leading to the synthesis of zinc-MT in the liver.
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MT Induction by Manganese in IL-6-Null Mice. To explore the direct evidence for the involvement of IL-6 in the induction of MT by manganese, we compared the MT induction between IL-6-null and wild-type mice. The induction of hepatic MT by the treatment with MnCl2 was completely suppressed in IL-6-null mice (Fig. 7). This is not caused by the suppression of manganese accumulation in IL-6-null mice because the peak levels of hepatic manganese 1 h after the treatment with MnCl2 (300 µmol/kg) were about the same in IL-6-null mice (58.1 ± 5.9 µg/g) and wild-type mice (69.6 ± 3.9 µg/g). Furthermore, the injection of human recombinant IL-6 (250 µg/kg) together with MnCl2 (300 µmol/kg) significantly recovered the induction of MT (35.7 ± 14.7 nmol of Hg2+ bound/g) in the liver of IL-6-null mice. These data further support the notion that IL-6 plays a crucial role in hepatic MT induction by MnCl2 treatment. Also, serum levels of SAA were completely suppressed in IL-6-null mice, suggesting that both hepatic MT induction and SAA production by the treatment with MnCl2 were completely dependent on IL-6. This is the first observation that the induction of MT by a metal compound is exclusively mediated by IL-6 production.
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Discussion |
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To elucidate the mechanism of MT induction by metal compounds, many studies have been focusing on the role of the transcription factor MTF-1 and metal-response elements (Andrews, 2001; Otsuka, 2004). The role of zinc ions in the activation of MTF-1 has been well characterized (Andrews, 2001; Jiang et al., 2003). However, potent MT-inducing metals such as cadmium or copper did not activate the DNA-binding activity of MTF-1 in a cell-free system (Bittel et al., 1998), suggesting that these metals activate MTF-1 indirectly via the release of zinc ions from intracellular zinc stores (Zhang et al., 2003). In addition, cadmium induces oxidative stress and produces several kinds of cytokines, both of which are known to induce the synthesis of MT. This suggests that mechanisms other than MTF-1 activation may also be involved in the induction of MT by cadmium (Chu et al., 1999). Thus, the molecular mechanisms of MT induction by nonzinc metal compounds still remain unclear.
Among MT-inducing metals, iron, chromium, cobalt, nickel, arsenic, and manganese are incapable of binding to MT protein. It has been postulated that these metals are indirect MT inducers and that the MT induction by these metals is mediated primarily by inflammation or stress responses. Because inflammatory cytokines such as IL-6, IL-1, and TNF- are known MT inducers (De et al., 1990; Penkowa and Hidalgo, 2000) and some metal compounds elicit allergic reactions, it is reasonable to assume that these cytokines are involved in MT induction by the nonspecific MT-inducing metals. However, the actual roles of these cytokines in MT induction by metal compounds have been poorly understood.
In previous studies, we have demonstrated that administration of the trivalent cerium compound, CeCl3 (Kobayashi et al., 2005), and pentavalent vanadium compound, ammonium metavanadate (Kobayashi et al., 2006), induced MT in the liver of mice, and this induction was significantly suppressed in IL-6-null mice compared with wild-type mice, indicating that IL-6 production by these metals is the major cause for the MT induction. Similar to manganese, cerium and vanadium compounds increased serum levels of IL-6 but not those of IL-1 or TNF-. In the present study, however, the administration of MnCl2 even at the highest dose did not increase serum activity of ALT (Fig. 3B), whereas the administration of CeCl3 or ammonium metavanadate in the previous studies caused dose-dependent increases in serum aspartate aminotransferase and ALT activities. Thus, the treatment of mice with MnCl2 enhanced the expression of IL-6 in the liver (Fig. 6A) without causing liver injury. Furthermore, MT induction by the administration of MnCl2 was completely suppressed in IL-6-null mice (Fig. 7A), whereas MT induction by cerium and vanadium compounds in IL-6-null mice was reduced to about one-half of that in wild-type mice (Kobayashi et al., 2005, 2006). These results suggest that factors other than IL-6 production are also involved in MT induction by hepatotoxic metals such as cerium and vanadium, whereas MT induction by nonhepatotoxic manganese in the liver is mediated exclusively by the production of IL-6.
It has been known that manganese is rapidly excreted into the bile from the liver when injected into animals (Klaassen, 1974). In the present study, we found little increase in the hepatic manganese concentration at 24 h after the administration (Fig. 1B), but the time-course experiment showed that a high concentration of manganese existed in the liver with a peak at 1.5 h (Fig. 4A). Probably this transient increase in manganese concentration in the liver caused the expression of the IL-6 gene in the liver with a peak at 3 h (Fig. 6A) either in Kupffer cells (Busam et al., 1990) or parenchymal hepatocytes (Saad et al., 1995). Subsequently, serum levels of IL-6 increased, with a peak at 6 h (Fig. 4B), and then the enhanced production of SAA (Fig. 4C) and MT synthesis followed in response to IL-6 stimulation. On the other hand, little increase in MT concentration was detected in the kidney even though high concentrations of manganese were accumulated in the kidney (Fig. 1). This may be due to the overwhelming abundance of IL-6 receptor in the liver compared with the kidney (Castell et al., 1988).
It is well known that serum levels of SAA, an acute-phase protein produced in the liver, are increased by inflammatory stimuli (Uhlar and Whitehead, 1999). Expression of the SAA gene is regulated primarily by inflammatory cytokines such as TNF-, IL-1, and IL-6 (Uhlar and Whitehead, 1999). In the present study, serum levels of IL-6 increased with a peak at 6 h after MnCl2 administration, and then the SAA levels increased and reached a maximum level at 24 h (Fig. 4). Furthermore, the increase in SAA levels by MnCl2 administration was completely suppressed in IL-6-null mice (Fig. 7B). These results suggest that the production of SAA by manganese is mediated solely by IL-6 production and is independent of liver injury.
Recently, several studies have demonstrated that IL-6-null mice exhibited more severe liver damage after the administration of lipopolysaccharide (Inoue et al., 2005), concanavalin A (Klein et al., 2005), and carbon tetrachloride (Kovalovich et al., 2000) than wild-type mice. These findings suggest the role of IL-6 or its downstream products in triggering the protective process against liver injury. Earlier studies have shown that treatment with manganese protected against hepatotoxicity induced by cadmium (Yoshikawa, 1970; Goering and Klaassen, 1985), suggesting that the MT induced by manganese is responsible for the attenuation of hepatotoxicity. However, we cannot exclude a possibility that manganese-induced IL-6 expression itself or its downstream products other than MT triggered the protection against hepatotoxicity. It is noteworthy that ME3738, an agent that induces IL-6 in the liver, protected against concanavalin A-induced hepatotoxicity (Kuzuhara et al., 2006). Further studies are warranted to clarify whether MT is the primary downstream product responsible for the IL-6-triggered cytoprotection or other non-MT factors induced by IL-6 are more important.
An early study reported that the MT induced by manganese in rat liver was coeluted with zinc in the gel filtration chromatography of liver supernatant (Suzuki and Yoshikawa, 1976). Waalkes et al. (1984) showed that manganese has no affinity for MT by using equilibrium dialysis in vitro. In the present study, the results of HPLC/ICP-MS analyses of liver cytosol showed more clearly that manganese was not bound to the MnCl2-induced MT, and zinc was the major metal binding to the MT (Fig. 2). Recently, Liuzzi et al. (2005) demonstrated that IL-6 induces hypozincemia through the activation of zinc transporter, ZIP14, which is responsible for the incorporation of zinc into the liver from the serum. As shown in Fig. 6B, the expression of ZIP14 was enhanced after the peak induction of IL-6 by MnCl2 treatment, suggesting that the enhanced incorporation of zinc from the extracellular pool via IL-6-activated ZIP14 expression might have contributed to the synthesis of zinc-MT in the liver. In support of this notion, very little increase in ZIP14 expression was detected in the liver of IL-6-null mice treated with MnCl2 (data not shown).
In conclusion, our study demonstrates that manganese induces hepatic MT synthesis completely depending on the production of IL-6 without accompanying liver injury. Further studies are warranted to clarify the mechanism underlying the specific activation of the IL-6 gene by manganese.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: MT, metallothionein; MTF-1, metal-responsive transcription factor 1; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; STAT, signal transducer and activator of transcription; ALT, alanine aminotransferase; BUN, blood urea nitrogen; SAA, serum amyloid A; ELISA, enzyme-linked immunosorbent assay; HPLC, high-performance liquid chromatography; ICP-MS, inductively coupled argon plasma-mass spectrometry; RT, reverse transcription; PCR, polymerase chain reaction; ME3738, 22-methoxyolean-12-ene-3,24(4)-diol.
Address correspondence to: Dr. Seiichiro Himeno, Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan. E-mail: himenos{at}ph.bunri-u.ac.jp
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) and wild-type (
) mice were treated s.c. with MnCl2, and the liver and blood samples were collected 24 h after the MnCl2 treatment. Concentrations of MT were determined by the Hg2+-binding assay (A), and concentrations of SAA were determined using a commercial ELISA kit (B). Values are means ± S.D. for five mice. ***, P < 0.001 versus control mice. ###, P < 0.001 versus wild-type mice.