Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense

DOI PDF 55 Citations
  • Peng Ye
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Fred H. Rodriguez
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Suzanne Kanaly
    bImmunex Corporation, Seattle, WA 98101
  • Kim L. Stocking
    bImmunex Corporation, Seattle, WA 98101
  • Jill Schurr
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Paul Schwarzenberger
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Peter Oliver
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Weitao Huang
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Ping Zhang
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Jason Zhang
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Judd E. Shellito
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Greg J. Bagby
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Steve Nelson
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112
  • Keith Charrier
    bImmunex Corporation, Seattle, WA 98101
  • Jacques J. Peschon
    bImmunex Corporation, Seattle, WA 98101
  • Jay K. Kolls
    aLouisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112

Abstract

<jats:p>Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4+ lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4+ T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R–deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.</jats:p>

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