Induction of metallothionein by manganese is completely dependent on interleukin-6 production.
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.
Kobayashi
Kazuo
K
Kissei Pharmaceutical co., Ltd., Nagano, Japan.
Kuroda
Junji
J
Shibata
Nobuo
N
Hasegawa
Tatsuya
T
Seko
Yoshiyuki
Y
Satoh
Masahiko
M
Tohyama
Chiharu
C
Takano
Hirohisa
H
Imura
Nobumasa
N
Sakabe
Kou
K
Fujishiro
Hitomi
H
Himeno
Seiichiro
S
D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology*; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008813:Mice, Inbred ICR; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology; D000097809:Transcription Factor MTF-1
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008345:Manganese; D008668:Metallothionein; D012333:RNA, Messenger; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C500556:SLC39A14 protein, mouse