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First published on October 25, 2006; DOI: 10.1124/jpet.106.112912

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Received for publication August 24, 2006.
Revised October 19, 2006.
Accepted for publication October 19, 2006.

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

Kazuo Kobayashi 1, Junji Kuroda 1, Nobuo Shibata 1, Tatsuya Hasegawa 2, Yoshiyuki Seko 2, Masahiko Satoh 3, Chiharu Tohyama 3, Hirohisa Takano 3, Nobumasa Imura 4, Kou Sakabe 4, Hitomi Fujishiro 5, Seiichiro Himeno 5*

1 Kissei Pharmaceutical Co., Ltd. 2 Yamanashi Institute of Environmental Sciences 3 National Institute for Environmental Studies 4 Kitasato University 5 Tokushima Bunri University

* Address correspondence to: E-mail: himenos{at}ph.bunri-u.ac.jp

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 manganese chloride (MnCl2) 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 MnCl2 caused the increase in mRNA levels of interleukin-6 (IL-6) in the liver as well as the 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 MnCl2 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.


Key words: induction, interleukin-6, liver, manganese, metallothionein, mouse




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