title: A Feedback Loop between Inflammation and Zn Uptake.
abstract: OBJECTIVE
  Zinc (Zn) has major effects on the immune system and inflammation is associated with systemic Zn deficiency. The aim of this work was to investigate how inflammation modifies Zn metabolism at the cellular level. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation. Osteoarthritis (OA) synoviocytes were used as control.
  
  
  METHODS
  Zn levels were measured in medium and inside cells by Induced Coupled Plasma-Mass Spectrometry (ICP-MS), in the presence of minute quantities of stable spike 70Zn isotope and the addition or not of the pro-inflammatory cytokines interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α). Gene expression of ZIP-8 importer, ZnT1 exporter and the homeostasis regulators metallothioneins (MTs) was evaluated after pre-exposure to cytokines, with or without exogenous Zn addition at increasing concentrations. IL-6 production was used as a marker of inflammation and measured by ELISA.
  
  
  RESULTS
  Exposure to IL-17 and TNF-α enhanced expression of the Zn-importer ZIP-8, regardless of the concentration of Zn in the culture medium. In contrast, the expression of the Zn-exporter ZnT1 and of the MTs was primarily dependent on Zn levels. Addition of Zn also increased the production of IL-6, thus further stimulating the inflammatory response.
  
  
  CONCLUSIONS
  IL-17/TNF-mediated inflammation enhanced the intracellular Zn uptake by synoviocytes, further increasing inflammation. These observations document the existence of a feedback loop between inflammation and Zn uptake. Based on these results, a mathematical model was developed to represent the cytokine-mediated Zn homeostasis alterations.
authors: Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Edouard Herriot Hospital, Lyon, 69437 France.
authors: Paola
authors: P
authors: Bonaventura
authors: Geology Laboratory-Department of Earth Sciences, Ecole Normale Supérieure de Lyon and CNRS Lyon, Lyon, 69364 France.
authors: Aline
authors: A
authors: Lamboux
authors: Geology Laboratory-Department of Earth Sciences, Ecole Normale Supérieure de Lyon and CNRS Lyon, Lyon, 69364 France.
authors: Francis
authors: F
authors: Albarède
authors: Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Edouard Herriot Hospital, Lyon, 69437 France.
authors: Pierre
authors: P
authors: Miossec
mesh_terms: D000465:Algorithms; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008954:Models, Biological; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; C017800:zinc-binding protein; D015032:Zinc