Shown to stabilize HIF-1 , but effects on inflammation were not assessed. GlyEnt also was reported to induce HIF-1 , but this necessary high concentrations of siderophores ( 200 M) (54).September 2014 Volume 82 Numberiai.asm.orgHolden et al.AEnterobactin Yersiniabactin Lipocalin 2 cytokinescytokinesBCIL-8 CCL20 Fe HIF-1 IL-6 Fe HIF-IL-8 CCL20 IL-FIG 7 Lcn2 acts as a sensor by modulating airway epithelial cell inflammatory cytokine secretion in response to iron chelation by unbound Ent and Ybt. (A) Compact amounts of Ent is often bound and neutralized by Lcn2, major to a low degree of Lcn2-induced cytokine secretion inside the airway. Large amounts of Ent (B) or Ybt (C) evade Lcn2 binding, top to altered host iron status and HIF-1 stabilization. The mixture of cellular iron depletion and Lcn2 signaling increases production of inflammatory cytokines, for example IL-8, IL-6, and CCL20.The present study demonstrates induction of HIF-1 stabilization by the prototypical siderophore Ent and Ent Lcn2 at physiologic concentrations. Furthermore, we illustrate that HIF-1 stabilization in combination with Lcn2 is adequate for IL-6 secretion, linking HIF-1 -regulated genes with inflammatory pathways. HIF-1 stabilization in combination with Lcn2 isn’t adequate to induce IL-8 or CCL20 secretion, suggesting that further pathways are activated in response to siderophore-Lcn2 stimulation that improve inflammation. IL-8 production by epithelial cells is regulated by a combination of MAPK and NF- B signaling pathways (18). Microarray analysis in response to remedy with Ent indicated upregulation of dual-specificity phosphatases (DUSPs), indicating that MAPK signaling is involved in IL-8 secretion in response to siderophore-Lcn2. In summary, our benefits introduce a novel function for Lcn2 as a rheostat that modulates the response to iron chelation by bacterial siderophores. We propose a model in which a modest level of Ent may be bound and neutralized by Lcn2 (Fig.152835-00-2 Data Sheet 7A), resulting in low levels of Lcn2-induced cytokine secretion. Nonetheless, high levels ofEnt (Fig. 7B) or Ybt (Fig. 7C) can overwhelm Lcn2 binding capacity, causing the accumulation of unbound siderophores. These siderophores chelate host cellular iron and, in mixture with Lcn2, induce robust secretion of IL-6, CCL20, and IL-8 in airway epithelial cells. Ent induces HIF-1 stabilization, and HIF-1 in combination with Lcn2 is enough to induce IL-6. In contrast, HIF-independent pathways most likely are essential to augment IL-8 and CCL20 expression.1,3,6,8-Tetrabromopyrene structure DFO and Ybt also combine with Lcn2 to induce inflammation, indicating this is a generalized response to siderophore-mediated iron starvation.PMID:22943596 In this way, Lcn2 can avoid iron sequestration by Ent without the need of triggering a substantial immune response but can potently upregulate inflammation when overwhelmed by siderophores that perturb epithelial cell iron homeostasis.ACKNOWLEDGMENTSThis study was supported by Public Health Service grant GM085612 from the National Institute of Basic Health-related Sciences (M.A.B.), CA148828 from the National Cancer Institute (Y.M.S.), and also a University of Michigan Rackham predoctoral grant (V.I.H.), and it was partially supported byiai.asm.orgInfection and ImmunitySiderophores with Lcn2 Induce Cytokine SecretionUniversity of Michigan Cancer Center Help grant P30 CA046592 from the National Institutes of Health (R.K.). We thank Harry Mobley, Marc Hershenson, and Beth Moore for guidance and manuscript revisions. We’ve no c.