TY - JOUR T1 - Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 721 LP - 727 DO - 10.1124/jpet.106.112912 VL - 320 IS - 2 AU - Kazuo Kobayashi AU - Junji Kuroda AU - Nobuo Shibata AU - Tatsuya Hasegawa AU - Yoshiyuki Seko AU - Masahiko Satoh AU - Chiharu Tohyama AU - Hirohisa Takano AU - Nobumasa Imura AU - Kou Sakabe AU - Hitomi Fujishiro AU - Seiichiro Himeno Y1 - 2007/02/01 UR - http://jpet.aspetjournals.org/content/320/2/721.abstract N2 - 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 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 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 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. The American Society for Pharmacology and Experimental Therapeutics ER -