Aspergillus fumigatus-induced interleukin-8 synthesis by respiratory epithelial cells is controlled by the phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2 pathways and not by the toll-like receptor-MyD88 pathway

J Biol Chem. 2008 Nov 7;283(45):30513-21. doi: 10.1074/jbc.M803149200. Epub 2008 Aug 14.

Abstract

Previous studies have established that phagocytes are key cells of the pulmonary innate immune defense against A. fumigatus, an opportunistic fungus responsible of invasive pulmonary aspergillosis. Macrophages detect A. fumigatus via Toll-like receptors 2 and 4 (TLR2 and -4) and respond by the MyD88-NF-kappaB-dependent synthesis of inflammatory mediators. In the present study, we demonstrate that respiratory epithelial cells also sense A. fumigatus and participate in the host defense. Thus, the interaction of respiratory epithelial cells with germinating but not resting conidia of A. fumigatus results in interleukin (IL)-8 synthesis that is controlled by phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2. Using MyD88-dominant negative transfected cells, we also show that IL-8 production is not dependent on the TLR-MyD88 pathway, although the MyD88 pathway is activated by A. fumigatus and leads to NF-kappaB activation. Thus, our results provide evidence for the existence of two independent signaling pathways activated in respiratory epithelial cells by A. fumigatus, one that is MyD88-dependent and another that is My88-independent and involved in IL-8 synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillus fumigatus / immunology
  • Aspergillus fumigatus / metabolism*
  • Cell Line
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / immunology
  • MAP Kinase Signaling System / immunology
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism*
  • Spores, Fungal / immunology
  • Spores, Fungal / metabolism*
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • CXCL8 protein, human
  • Inflammation Mediators
  • Interleukin-8
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases