IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro.

Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA.
The Journal of Immunology (Impact Factor: 5.36). 03/2011; 186(5):3197-205. DOI: 10.4049/jimmunol.1002016
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR(+) CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR(+) CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS. © 2015 Rumble et al.
    Journal of Experimental Medicine 01/2015; 212(1). DOI:10.1084/jem.20141015 · 13.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. TNFα antagonists are effective for treating rheumatoid arthritis and other inflammatory diseases, but their use can be complicated by lupus-like phenomena. We investigated the role of TNFα in murine lupus.Methods. TLR7 ligand-driven lupus was induced in B6 and B6- TNFα-/- mice using pristane. Autoantibodies and type I interferon (IFN-I) production were measured and the effects on IFN-I-producing plasmacytoid dendritic cells (pDCs), Ly6Chi monocytes, and TNFα-producing neutrophils were determined.Results. TNFα-/- mice did not spontaneously develop autoantibodies or clinical manifestations, suggesting that TNFα deficiency alone is insufficient to cause lupus. Although IFN-I levels were comparable in untreated TNFα-/- and B6 mice, untreated TNFα-/- mice had increased circulating pDCs and “pDC-like” cells, enhancing their potential to make IFN-I. When treated with pristane, TNFα-/- mice developed more severe lupus than controls with increased levels of anti-Sm/RNP autoantibodies, IFN-I, pDCs, and peritoneal inflammatory (Ly6Chi) monocytes. Neutrophils, which promoted resolution of inflammation, were decreased considerably in pristane-treated TNFα-/- mice, whereas the inflammatory monocyte and pDC responses and IFN-I were increased and prolonged.Conclusions. Low levels of TNFα increased circulating pDC numbers, enhancing the potential to make IFN-I. But this did not lead to IFN-I production or autoimmunity unless there was concomitant exposure to endogenous TLR7 ligands released from dead cells following pristane treatment. In patients, the rate of clearance of dead cells along with TNFα levels may influence who will develop lupus when treated with TNFα inhibitors. © 2014 American College of Rheumatology.
    09/2014; DOI:10.1002/art.38882
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study was conducted to explore the anti-inflammatory effect of Jungia sellowii (Asteraceae) using a murine model of pleurisy induced by carrageenan (Cg). This plant is used in southern Brazil to treat inflammatory diseases. J. sellowii leaves were extracted with ethanol/water to obtain the crude extract (CE), which was fractionated with different solvents, yielding n-hexane (Hex), dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol (BuOH) fractions, and aqueous fraction (Aq). The major compounds succinic acid (SA) and lactic acid (LA) were isolated from Aq fraction, and their structures were determined by (1)H and (13)C NMR. Pleurisy was induced by Cg (Saleh et al. 1996). The leukocytes, exudation, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities, metabolites of nitric oxide (NO x ) levels, protein levels and mRNA expression for interleukin 1 beta (IL-1β), tumour necrosis factor alpha (TNF-α), interleukin 17A (IL17A) and inducible of nitric oxide synthase (iNOs), and p65 protein phosphorylation (NF-κB) were analysed 4 h after pleurisy induction. Animals pre-treated with CE, BuOH, Aq, SA, or LA inhibited leukocytes, exudation, MPO and ADA activities, NO x , IL-1β, TNF-α, and IL-17A levels, and the mRNA expression for IL-1β, TNF-α, IL-17A, iNOS, and p65 protein phosphorylation (NF-κB) (p < 0.05). Our study demonstrated that J. sellowii can protect against inflammation induced by Cg by decreasing the leukocytes and exudation. Its effects are related to the decrease of either proinflammatory cytokines and/or NO x . The isolated compounds SA and LA may play an important role in this anti-inflammatory action by inhibiting all the studied parameters. The anti-inflammatory properties of these compounds are due to the downregulation of NF-κB.
    Inflammopharmacology 08/2014; 22(6). DOI:10.1007/s10787-014-0210-3

Full-text (2 Sources)

Available from
Jun 4, 2014