n-Hexane-Induced Synthesis of Hepatic Metallothionein Is Mediated by IL-6 in Mouse

Itoh, Norio; Okamoto, Hirotsugu; Ohta, Mitsue; Hori, Takamitsu; Min, Kyung‐Jin; Onosaka, Satomi; Nakanishi, H; Okabe, Masaru; Muto, Norio; Tanaka, Kinji

doi:10.1006/taap.1994.1030

Cited by 15 publications

(6 citation statements)

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“…To date, various agents such as organic solvent, endotoxin, hormones, and cytokines have been shown to induce MT in animals and cells. [18][19][20][21][22] Inflammation or physical stress involves the induction of cytokines such as IL-1b, IL-6, TNF-a and IFN-g. These cytokines are also inducers of MT in the liver of animals and hepatic cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of Hepatic Metallothionein by Trivalent Cerium: Role of Interleukin 6

Kobayashi

Shida

Hasegawa³

et al. 2005

Biological & Pharmaceutical Bulletin

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Metallothionein (MT) is a small sulfydryl-rich protein that binds to and is inducible by heavy metals such as mercury, cadmium, zinc, and copper. However, little is known about the induction of MT by trivalent metals except for bismuth. In this study, we examined the induction of MT synthesis by cerium, a trivalent lanthanoid metal. Administration of cerium chloride (CeCl3) to mice resulted in accumulation of cerium and induction of MT in the liver in a dose-dependent manner. Distribution profiles of metals in the soluble fraction of the liver of CeCl3-treated mice analyzed by high performance liquid chromatography/inductively coupled argon plasma-mass spectrometry (HPLC/ICP-MS) demonstrated that the metal bound to MT-I and MT-II was zinc, but not cerium. Administration of CeCl3 caused increases in the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of serum amyloid A (SAA), an acute phase protein. Among inflammatory cytokines examined, interleukin 6 (IL-6) exhibited a marked increase in the serum at 3 h after the CeCl3 administration. In order to evaluate the involvement of IL-6 in the induction of MT by cerium, we examined MT induction by CeCl3 in IL-6 null mice. Both the induction of hepatic MT and the increases in SAA levels were markedly suppressed in IL-6 null mice. These results suggest that IL-6 plays an important role in the induction of hepatic MT by cerium.

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Section: Discussionmentioning

confidence: 99%

Induction of Hepatic Metallothionein by Trivalent Cerium: Role of Interleukin 6

Kobayashi

Shida

Hasegawa³

et al. 2005

Biological & Pharmaceutical Bulletin

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“…Recent studies demonstrate that antiserum against IL-6 can block the ability of serum from LPS-treated mice to induce expression of MT in a hepatoma cell line [24], and IL-6 has been shown to induce MT gene expression in rat hepatocyte cultures [25,26]. Remarkably, IL-6 has also been suggested to play a key role in hepatic MT gene expression during inflammation caused by organic solvents [23] and by immobilization stress (J. Carrasco, J. Hernandez, H. Bluethmann, G. K. Andrews and J. Hidalgo, unpublished work).…”

Section: Discussionmentioning

confidence: 99%

“…Injection of a variety of cytokines, such as IL-1, IL-6, TNF-α and interferon (IFN), can induce hepatic MT gene expression in i o [18,[20][21][22]. IL-6 has been suggested to be a direct mediator of hepatic MT gene expression in mice [18,[22][23][24]. Studies of rat hepatocytes cultured in itro support the concept that IL-6, in combination with zinc and glucocorticoids, directly mediates MT gene expression during inflammation [25,26].…”

Section: Introductionmentioning

confidence: 99%

Identification of a signal transducer and activator of transcription (STAT) binding site in the mouse metallothionein-I promoter involved in interleukin-6-induced gene expression

et al. 1999

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Mechanisms of regulation of mouse metallothionein (MT)-I gene expression in response to bacterial endotoxin-lipopolysaccharide (LPS) were examined. Northern blot analysis of hepatic MT-I mRNA in interleukin (IL)-6 or tumour necrosis factor (TNF)-receptor type I knock-out mice demonstrated that IL-6, not TNF-alpha, is of central importance in mediating hepatic MT-I gene expression in vivo after LPS injection. In vivo genomic footprinting of the MT-I promoter demonstrated a rapid increase, after LPS injection, in the protection of several guanine residues in the -250 to -300 bp region of the MT-I promoter. The protected bases were within sequences which resemble binding sites for the signal transducers and activators of transcription (STAT) transcription factor family. Electrophoretic mobility-shift assays using oligonucleotides from footprinted MT-I promoter regions showed that injection of LPS resulted in a rapid increase in the specific, high-affinity, in vitro binding of STAT1 and STAT3 to a binding site at -297 bp (TTCTCGTAA). Western blotting of hepatic nuclear proteins showed that the time-course for changes of total nuclear STAT1 and STAT3 after LPS injection paralleled the increased complex formation in vitro using this oligonucleotide, and binding was specifically competed for by a functional STAT-binding site from the rat alpha2-macroglobulin promoter. Furthermore, the MT-I promoter -297 bp STAT-binding site conferred IL-6 responsiveness in the context of a minimal promoter in transient transfection assays using HepG2 cells. This study suggests that the effects of LPS on hepatic MT-I gene expression are mediated by IL-6 and involve the activation of STAT-binding to the proximal promoter.

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“…Recent studies have demonstrated that the induction of hepatic MT synthesis by radical inducing nonmetallic compounds is associated with an acute-phase response in inflammation in which varying species of cytokines are involved (Min et al 1991). Glucocorticoids inhibited the induction of MT synthesis during inflammation by suppressing cytokine production (Min et al 1992b;Itoh et al 1994). However, the present data showed that hepatic MT level induced by PQ in GSH-depleted mice was increased synergetically by dexamethasone pretreatment, whereas dexamethasone pretreatment significantly reduced the increase of MT level caused by injection of turpentine oil.…”

Section: Discussionmentioning

confidence: 99%

Effect of Glutathione Depletion on Metallothionein Synthesis Induced by Paraquat in Mice.

Nakagawa

Suzuki

Yanagiya

et al. 1995

Tohoku J. Exp. Med.

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The effect of Glutathione (0511) depletion on the induction of metallothionein (MT) synthesis by paraquat (PQ) was examined in ICR mice. An increase in hepatic MT level in mice was observed after a single PQ administration. Pretreatment of mice with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, enhanced the induction of hepatic and renal MT synthesis by PQ depending on the decreased tissue GSH level. A similar result was obtained by pretreatment with diethylmaleate, a GSH depleting agent. The ratio of hepatic MT-I to MT-II induced by PQ was not changed by BSO pretreatment. An increase in the hepatic MT level in GSH depleted mice was observed from 3 hr to 24 hr after PQ administration. An increase in the hepatic MT-I mRNA level after treatment with PQ was observed prior to hepatic MT induction in BSO pretreated mice. Pretreatment with actinomycin D, an inhibitor of mRNA synthesis, inhibits the PQ-induced increase in hepatic MT and MT-I mRNA levels in BSO pretreated mice. Pretreatment with BSO did not affect the induction of MT synthesis by zinc, cadmium or dexamethasone. Pretreatment with dexamethasone, an anti-inflammatory agent, enhanced the hepatic MT induction by PQ treatment in GSH depleted mice, while dexamethasone reduced the MT induction by turpentine oil, which is known to induce inflammation and hepatic MT synthesis. These findings suggest that GSH depletion enhances the induction of MT synthesis by PQ because of an increase in the transcription rate, and this enhancement of MT synthesis is not due to an inflammatory response caused by PQ. glutathione depletion; metallothionein; paraquat

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n-Hexane-Induced Synthesis of Hepatic Metallothionein Is Mediated by IL-6 in Mouse

Cited by 15 publications

References 0 publications

Induction of Hepatic Metallothionein by Trivalent Cerium: Role of Interleukin 6

Induction of Hepatic Metallothionein by Trivalent Cerium: Role of Interleukin 6

Identification of a signal transducer and activator of transcription (STAT) binding site in the mouse metallothionein-I promoter involved in interleukin-6-induced gene expression

Effect of Glutathione Depletion on Metallothionein Synthesis Induced by Paraquat in Mice.

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