Resistance to Pseudomonas aeruginosa Chronic Lung Infection Requires Cystic Fibrosis Transmembrane Conductance Regulator-Modulated Interleukin-1 (IL-1) Release and Signaling through the IL-1 Receptor
| Autor: | Martin M. Lee, Christopher Ray, Fadie T. Coleman, Gerald B. Pier, Nina Reiniger, David E. Golan |
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| Rok vydání: | 2007 |
| Předmět: |
Interleukin-1beta
Immunology Cystic Fibrosis Transmembrane Conductance Regulator Mice Inbred Strains medicine.disease_cause Microbiology Cystic fibrosis Cell Line Mice Immunity medicine Animals Humans Pseudomonas Infections Lung Cell Nucleus Mice Knockout Host Response and Inflammation Microscopy Confocal Innate immune system biology Pseudomonas aeruginosa Diptera NF-kappa B Receptors Interleukin-1 medicine.disease Immunity Innate Toll-Like Receptor 2 Cystic fibrosis transmembrane conductance regulator Toll-Like Receptor 4 Toll-Like Receptor 5 TLR2 Infectious Diseases TLR5 Myeloid Differentiation Factor 88 biology.protein TLR4 Parasitology |
| Zdroj: | Infection and Immunity. 75:1598-1608 |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.01980-06 |
| Popis: | Innate immunity is critical for clearing Pseudomonas aeruginosa from the lungs. In response to P. aeruginosa infection, a central transcriptional regulator of innate immunity—NF-κB—is translocated within 15 min to the nuclei of respiratory epithelial cells expressing wild-type (WT) cystic fibrosis (CF) transmembrane conductance regulator (CFTR). P. aeruginosa clearance from lungs is impaired in CF, and rapid NF-κB nuclear translocation is defective in cells with mutant or missing CFTR. We used WT and mutant P. aeruginosa and strains of transgenic mice lacking molecules involved in innate immunity to identify additional mediators required for P. aeruginosa -induced rapid NF-κB nuclear translocation in lung epithelia. We found neither Toll-like receptor 2 (TLR2) nor TLR4 nor TLR5 were required for this response. However, both MyD88-deficient mice and interleukin-1 receptor (IL-1R)-deficient mice failed to rapidly translocate NF-κB to the nuclei of respiratory epithelial cells in response to P. aeruginosa . Cultured human bronchial epithelial cells rapidly released IL-1β in response to P. aeruginosa ; this process was maximized by expression of WT-CFTR and dramatically muted in cells with ΔF508-CFTR. The IL-1R antagonist blocked P. aeruginosa -induced NF-κB nuclear translocation. Oral inoculation via drinking water of IL-1R knockout mice resulted in higher rates of lung colonization and elevated P. aeruginosa -specific antibody titers in a manner analogous to that of CFTR-deficient mice. Overall, rapid IL-1 release and signaling through IL-1R represent key steps in the innate immune response to P. aeruginosa infection, and this process is deficient in cells lacking functional CFTR. |
| Databáze: | OpenAIRE |
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