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

Abstract

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

A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

“…Bacteria are thought to contain high-affinity zinc transporters as a strategy to overcome zinc limitation during infection in which the acute phase response has been shown to result in reduced plasma zinc concentrations (20,38) with upregulation and release of the zinc binding complex calprotectin in the blood and lungs (29,31,55). In accord with this hypothesis, we demonstrated here that H. influenzae requires a specialized high-affinity zinc utilization pathway for virulence.…”

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

“…Nukina et al showed that the plasma IL-6 level peaked at 1 h after the onset of restraint stress in the mouse but they did not measure the value at 3 h (Nukina et al 2001). After this serum IL-6 elevation, mRNA of Zip14, an IL-6 responsive zinc transporter which facilitates extracellular zinc into cytosol (Liuzzi et al 2005), was induced about 12-fold at 6 h after the onset of restraint stress (Fig. 2a), followed by the increase in the zinc concentration in the liver (Fig.…”

“…ZIP members facilitate zinc influx into the cytosol, while CDF members facilitate its efflux from the cytosol. Abundance of Zip14, one of the ZIP family transporters, in the plasma membrane of hepatocytes is induced after turpentine-induced inflammation and lipopolysaccharide administration (Liuzzi et al 2005). IL-6 is considered to be the main proinflammatory cytokine regulating acute-phase genes and Zip14 expression is up-regulated through IL-6.…”

“…Transfection of Zip14 cDNA into human embryonic kidney cells increased zinc uptake, suggesting that Zip14 functions as a zinc importer. Zip14 has been suggested to play a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection (Liuzzi et al 2005).…”

Measuring zinc on the Roche cobas c502 analyzer—Validation, comparison, and pre‐analytic aspects

“…8 Zinc status in patient with suspected zinc deficiency can be assessed from several biological materials with the most common being plasma/serum blood samples or urine samples. 9 However, plasma/serum zinc status is not only influenced by zinc deficiency, also inflammation can lower plasma zinc levels 10 and as such interpretation of plasma zinc levels is not always straightforward. 11,12 Methods for the analysis of plasma or serum zinc concentrations range from atomic absorption spectrophotometry over mass spectrometry to the more commonly used photometry.…”