title: Interleukin-1beta contributes via nitric oxide to the upregulation and functional activity of the zinc transporter Zip14 (Slc39a14) in murine hepatocytes.
abstract: Zinc metabolism during chronic disease is dysregulated by inflammatory cytokines. Experiments with IL-6 knockout mice show that LPS regulates expression of the zinc transporter, Zip14, by a mechanism that is partially independent of IL-6. The LPS-induced model of sepsis may occur by a mechanism signaled by nitric oxide (NO) as a secondary messenger. To address the hypothesis that NO can modulate Zip14 expression, we treated primary hepatocytes from wild-type mice with the NO donor S-nitroso N-acetyl penicillamine (SNAP). After treatment with SNAP, steady-state Zip14 mRNA levels displayed a maximal increase after 8 h and a concomitant increase in the transcriptional activity of the gene. Chromatin immunoprecipitation documented the kinetics of activator protein (AP)-1 and RNA polymerase II association with the Zip14 promoter after NO exposure, indicating a role of AP-1 in transcription of Zip14. We then stimulated the primary murine hepatocytes with IL-1beta, an LPS-induced proinflammatory cytokine and a potent activator of inducible NO synthase (iNOS) and NO production. In support of our hypothesis, IL-1beta treatment led to a threefold increase in Zip14 mRNA and enhanced zinc transport, as measured with a zinc fluorophore, in wild-type but not iNOS-/- hepatocytes. These data suggest that signaling pathways activated by NO are factors in the upregulation of Zip14, which in turn mediates hepatic zinc accumulation and hypozincemia during inflammation and sepsis.
authors.affiliation: Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA.
authors.forename: Louis A
authors.initials: LA
authors.lastname: Lichten
authors.forename: Juan P
authors.initials: JP
authors.lastname: Liuzzi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cousins
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D027682:Cation Transport Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C500556:SLC39A14 protein, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II