N of a limited set of cytokines, namely, IL-6, IL-8, and CCL20. These findings also indicate a novel mechanism for siderophore-induced cytokine secretion, linking HIF-1 stabilization by pathogen-associated siderophores to IL-6 secretion. With out its ligand, Lcn2 has been shown to modulate cytokine expression. In cells on the central nervous system, Lcn2 modulates lipopolysaccharide-induced cytokine production, including IL-6 and CCL20, as well as adipokine production in adipocytes (39, 40). In models of ischemia and reperfusion, Lcn2 controls neutrophil recruitment by regulating expression of chemokines, like IL-6, and their cell surface receptors (41). Consistent with these research, our findings indicate that Lcn2 induces IL-6 and CCL20 secretion from respiratory epithelial cells. IL-6 is aninflammatory cytokine active within the regulation of your acutephase response in hepatocytes and is capable of upregulating expression of hepcidin (42). Hepcidin regulates plasma iron concentrations by inhibiting enterocyte uptake of iron and iron recycling by macrophages and is upregulated during infection and inflammation (43). IL-6 is also a differentiation element for Th17 lymphocytes that mediate protective immunity against siderophore-producing pathogens, including K.127094-57-9 site pneumoniae (44).64325-78-6 Data Sheet In turn, CCL20 is really a lymphocyte chemoattractant whose expression is amplified by IL-6 production, recruiting Th17 cells to web-sites of inflammation by binding to its cognate receptor, CCR6. Thus, it really is doable that expression of CCL20 initiates an adaptive immune response (45?7). Lcn2-induced cytokines also are induced in response to disruptions in iron homeostasis. Iron chelation by DFO induces IL-iai.asm.orgInfection and ImmunitySiderophores with Lcn2 Induce Cytokine SecretionFIG 6 Ent stabilizes HIF-1 in A549 respiratory epithelial cells, that is sufficient to enhance Lcn2-dependent IL-6 secretion. Cells have been stimulated for 16 h with combinations of 50 M Ent, three mM DMOG, or 25 M Lcn2, and Western blotting or ELISA was utilized to measure HIF-1 stabilization (A, B, and C), IL-8 secretion (D), or IL-6 secretion (E).PMID:23776646 Western blot data are representative of 2 independent experiments. ELISA values shown are suggests SEM from 3 replicate samples and are representative of a minimum of two independent experiments. Statistics have been calculated making use of unpaired two-tailed t tests (**, P 0.01; ns, P 0.05).and CCL20 production in intestinal epithelial cells (17, 48). In respiratory epithelial cells, the mixture of siderophores and Lcn2 induces robust expression of IL-6 and CCL20. For that reason, the cytokine response to bacterial siderophores and Lcn2 could serve as a multifaceted failsafe mechanism. 1st, IL-8 can recruit neutrophils for the web-site of infection. Second, IL-6 can upregulate hepcidin to limit further iron availability for invading bacteria. Finally, IL-6 and CCL20 can act in concert to attract mature Th17 to websites of infection and commit naive T cells for the Th17 pathway. The presence or absence of siderophores likely is important for the impact of Lcn2 on inflammation. In recent operate, stimulation of macrophages with Streptococcus pneumoniae induced IL-10 production in an Lcn2-dependent manner, which skewed macrophages toward a deactivated phenotype (49). In human and animal models, improved Lcn2 correlated with worsening of pneumococcal pneumonia. These findings contrast with the outcomes of this operate, which demonstrate proinflammatory effects ofLcn2, and earlier perform by our group.
