Metallothionein Induction by Restraint Stress: Role of Glucocorticoids and Il-6

Hernández, Jesús Avilla; Carrasco, Javier; Belloso, Eva; Giralt, Mercedes; Bluethmann, Horst; Lee, Daekee; Andrews, Glen K.; Hidalgo, Juan

doi:10.1006/cyto.1999.0629

Cited by 50 publications

(38 citation statements)

References 26 publications

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“…Evidence is available suggesting that the binding sites of MT, particularly those that comprise the N-terminal (␤-cluster) metal-binding domain of the protein (24), may be the ultimate recipients of zinc ions lost from the plasma pool during stress and inflammation. Although IL-6 has been shown to enhance the induction of MT in hepatocytes (8,9,25), our data presented here suggest that both Zip14 and MT are components of the IL-6-mediated hypozincemia. Clearly, mice that cannot make IL-6 are not capable of lowering serum zinc concentrations during turpentine-induced inflammation.…”

Section: Discussioncontrasting

confidence: 73%

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Liuzzi

Lichten²,

Rivera³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

496

395

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Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6 ؊/؊ ) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6 ؊/؊ mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn 2؉ and 65 Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.endotoxemia ͉ inflammation ͉ hepatic ͉ Slc39a14 ͉ knockout mice

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Section: Discussioncontrasting

confidence: 73%

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Liuzzi

Lichten²,

Rivera³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

496

395

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“…The most over-represented networks were shown to be those involved in apoptosis. Confirmation of the array data by quantitative PCR revealed that GR overexpression in SCLC cells resulted in a twofold upregulation of the proapoptotic genes, BCL2-antagonist of cell death (BAD) and BCL2-associated X protein (BAX) (Figure 8a) as well as upregulation of metallothionein 1X (MT1X), a well-characterized GR responsive marker gene (Hernandez et al, 2000). Furthermore, upregulation of BAD was confirmed at the protein level by immunocytochemistry (Figure 8c and d).…”

Section: Glucocorticoid Receptors In Sclc P Sommer Et Almentioning

confidence: 61%

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

et al. 2007

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“…Metallothioneins, zinc-binding proteins that act to detoxify heavy metals, act as a free radical scavenger protecting cells from reactive oxygen species (Hidalgo et al 1988). Induction of metallothioneins in the liver by restraint stress is also mediated by IL-6 (Hernandez et al 2000). Elevation of zinc concentration and induction of metallothionein in the liver under restraint stress may play a key role in protecting the liver from stress-inducible injury.…”

Section: Discussionmentioning

confidence: 99%

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

et al. 2008

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The zinc concentration in the liver was significantly higher in mice at 12 h after the onset of restraint stress than that without stress. The IL-6 protein level in the serum was transiently elevated at 3 h after the onset of restraint stress, and the IL-6-responsive zinc transporter Zip14 mRNA in the liver was expressed markedly at 6 h. These results suggest that Zip14 plays a major role in the mechanism responsible for accumulation of zinc in the liver under restraint stress.

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Metallothionein Induction by Restraint Stress: Role of Glucocorticoids and Il-6

Cited by 50 publications

References 26 publications

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

Restraint stress up-regulates expression of zinc transporter Zip14 mRNA in mouse liver

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