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.
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.
Balloy
Viviane
V
Unité de Défense Innée et Inflammation, Institut Pasteur, Paris 75015, France.
Sallenave
Jean-Michel
JM
Wu
Yongzheng
Y
Touqui
Lhousseine
L
Latgé
Jean-Paul
JP
Si-Tahar
Mustapha
M
Chignard
Michel
M
D001232:Aspergillus fumigatus / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D013172:Spores, Fungal / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
D018836:Inflammation Mediators; D016209:Interleukin-8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; C508606:CXCL8 protein, human; C507779:MYD88 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human