Liu, Y. et al. IL-17A and TNF-alpha exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J. Immunol. 186, 3197-3205

Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2011; 186(5):3197-205. DOI: 10.4049/jimmunol.1002016
Source: PubMed


CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-α, we hypothesized that IL-17A would enhance TNF-α-induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-α in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-α and IL17A were greatly attenuated in Cxcl5(-/-) mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild-type mice. Bone marrow chimeras produced using Cxcl5(-/-) donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-α-induced CXCL5 transcription and stabilized TNF-α-induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-κB, IL-17A did not increase TNF-α-induced NF-κB activation. Apical costimulation of IL-17A and TNF-α provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimulation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury.

Download full-text


Available from: Linda Gonzales,
47 Reads
  • Source
    • "Similar to our previous reports [9,11,12], we clearly observed mixed Th2/Th17 airway inflammation, including the recruitment of neutrophils and eosinophils, in NO2-promoted allergic airway disease. Neutrophil recruitment required IL-17A, likely through the induction of Cxcl5 by pulmonary epithelial cells [67], validating that IL-17A is a critical contributor to airway neutrophila in NO2-promoted allergic airway disease [68]. However, contrary to our hypothesis, treatment with an IL-17A-neutralizing antibody did not impact the development of MCh hyperresponsiveness compared to untreated NO2-sensitized and challenged mice and resulted in increased elastance compared to mice administered and isotype control antibody. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated.
    PLoS ONE 09/2013; 8(9):e74730. DOI:10.1371/journal.pone.0074730 · 3.23 Impact Factor
  • Source
    • "Consistent with our findings, previous results in the literature have demonstrated the ability of vitexin to inhibit TNF-a release in the experimental model of ischemia/ reperfusion injury in rats (Dong et al. 2011). The anti-inflammatory effect obtained by inhibition of both cytokines supports the findings of previous studies that observed a synergistic effect of TNF-a and IL-17 on neutrophil recruitment in acute lung injury using an in vivo assay of Escherichia coli pneumonia model in mice and an in vitro alveolar and endothelium cell culture experiments (Liu et al. 2011; Griffin et al 2012). Our results agree with those of others in the literature demonstrating that vitexin has been found to be an effective anti-inflammatory flavonoid by decreasing TNF-a and IL-1b levels and attenuating the expression of the p65 subunit of NF-jB in the experimental rat model of ischemia/reperfusion (Dong et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate the anti-inflammatory effect of the crude hydroalcoholic extract (CHE) from the aerial parts of Croton antisyphiliticus, its fractions and isolated compounds derived from it on the mouse model of pleurisy induced by carrageenan. The aerial parts of C. antisyphiliticus were dried, macerated and extracted with ethanol to obtain the CHE, which was fractionated by liquid-liquid extraction using solvents with increasing polarity to obtain hexane (Hex), ethyl acetate (EA) and aqueous (Aq) fractions. Vitexin and quinic acid were isolated from Aq fraction. Capillary electrophoresis analysis, physical characteristics and spectral data produced by infrared (IR), nuclear magnetic resonance ((1)H and (13)C NMR) and mass spectrometry analyses were used to identify and elucidate the structure of the isolated compounds. The experimental model of pleurisy was induced in mice by a single intrapleural injection of carrageenan (1 %). Leukocytes, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities and nitrate/nitrite (NOx), tumor necrosis factor-α (TNF-α) and interleukin-17 (IL-17) levels were determined in the pleural fluid leakage at 4 h after pleurisy induction. Animals pre-treated with CHE, Hex, EA, Aq, vitexin and quinic acid exhibited decreases in leukocytes, exudate concentrations, MPO and ADA activities and NOx levels (p < 0.05). Also CHE, Hex, EA and vitexin but not quinic acid inhibited TNF-α and IL-17 levels (p < 0.05). C. antisyphiliticus caused anti-inflammatory effect by inhibiting the activated leukocytes, exudate concentrations, NOx, TNF-α, and IL-17 levels. The compounds vitexin and quinic acid may be responsible for this anti-inflammatory action.
    Inflammopharmacology 08/2013; 22(2). DOI:10.1007/s10787-013-0184-6
  • Source
    • "Foxm1 promotes pulmonary fibrosis D Balli et al inflammation and fibrosis (Rose et al, 2003; Wilson et al, 2010; Liu et al, 2011), were increased while Ccl3 was not changed (Supplementary Figure 3C). Cotransfection of CMV– Foxm1b expression vector significantly increased transcriptional activity of the À 1.3 Kb Ccl2 and the À 1.14 Kb Cxcl5 promoter regions in a luciferase reporter assay in vitro (Supplementary Figure 3D). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alveolar epithelial cells (AECs) participate in the pathogenesis of pulmonary fibrosis, producing pro-inflammatory mediators and undergoing epithelial-to-mesenchymal transition (EMT). Herein, we demonstrated the critical role of Forkhead Box M1 (Foxm1) transcription factor in radiation-induced pulmonary fibrosis. Foxm1 was induced in AECs following lung irradiation. Transgenic expression of an activated Foxm1 transcript in AECs enhanced radiation-induced pneumonitis and pulmonary fibrosis, and increased the expression of IL-1β, Ccl2, Cxcl5, Snail1, Zeb1, Zeb2 and Foxf1. Conditional deletion of Foxm1 from respiratory epithelial cells decreased radiation-induced pulmonary fibrosis and prevented the increase in EMT-associated gene expression. siRNA-mediated inhibition of Foxm1 prevented TGF-β-induced EMT in vitro. Foxm1 bound to and increased promoter activity of the Snail1 gene, a critical transcriptional regulator of EMT. Expression of Snail1 restored TGF-β-induced loss of E-cadherin in Foxm1-deficient cells in vitro. Lineage-tracing studies demonstrated that Foxm1 increased EMT during radiation-induced pulmonary fibrosis in vivo. Foxm1 is required for radiation-induced pulmonary fibrosis by enhancing the expression of genes critical for lung inflammation and EMT.
    The EMBO Journal 01/2013; 32(2). DOI:10.1038/emboj.2012.336 · 10.43 Impact Factor
Show more