T 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 mixture with Lcn2 just isn’t sufficient to induce IL-8 or CCL20 secretion, suggesting that more ACAT1 review pathways are activated in response to siderophore-Lcn2 stimulation that enhance inflammation. IL-8 production by epithelial cells is regulated by a mixture 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 role for Lcn2 as a rheostat that modulates the response to iron chelation by bacterial siderophores. We propose a model in which a tiny volume of Ent is usually bound and neutralized by Lcn2 (Fig. 7A), resulting in low levels of Lcn2-induced cytokine secretion. Nevertheless, higher 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 combination 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 mixture with Lcn2 is adequate to induce IL-6. In contrast, HIF-independent pathways probably are necessary to augment IL-8 and CCL20 expression. DFO and Ybt also combine with Lcn2 to induce inflammation, indicating this is a generalized response to siderophore-mediated iron starvation. In this way, Lcn2 can protect against iron sequestration by Ent with out 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 in the National Institute of General Healthcare Sciences (M.A.B.), CA148828 from the National Cancer Institute (Y.M.S.), and 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 in the National Institutes of Well being (R.K.). We thank Harry Mobley, Marc Hershenson, and Beth Moore for guidance and manuscript revisions. We’ve no conflicting economic interests to report.
ResearchAuthor’s Option?2014 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is offered on line at Virus Protease Inhibitor Compound mcponline.orgProteomic Analysis of Altered Extracellular Matrix Turnover in Bleomycin-induced Pulmonary FibrosisSMartin L. Decaris, Michelle Gatmaitan, Simplicia FlorCruz, Flora Luo, Kelvin Li, William E. Holmes, Marc K. Hellerstein? Scott M. Turner, and Claire L. EmsonFibrotic illness is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Surprisingly, very little is known about the synthesis and degradation prices from the numerous proteins and proteoglycans that constitute healthful or pathological extracellular matrix. A comprehensive understanding of altered ECM protein synthesis and degradation in the course of the onset and progression of fibrotic illness could be immensely precious. We have developed a dynamic proteomics platform that quantifies the fractional synthesis prices of massive numbers of proteins by means of stable isotope labeling and LC/MS-based mass iso.