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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 ^,

Nina Reiniger,^1,2, Martin M. Lee,^1,2, Fadie T. Coleman,^1,2 Christopher Ray,^1,2 David E. Golan,^1,3,4 and Gerald B. Pier^1,2*

Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115,¹ Channing Laboratory and,² Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115,³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115⁴

Received 18 December 2006/ Returned for modification 24 January 2007/ Accepted 29 January 2007

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-B—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-B 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-B 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-B to the nuclei of respiratory epithelial cells in response to P. aeruginosa. Cultured human bronchial epithelial cells rapidly released IL-1ß in response to P. aeruginosa; this process was maximized by expression of WT-CFTR and dramatically muted in cells with F508-CFTR. The IL-1R antagonist blocked P. aeruginosa-induced NF-B 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.

Published ahead of print on 5 February 2007.

Editor: A. D. O'Brien

Supplemental material for this article may be found at http://iai.asm.org/.

Present address: Columbia Presbyterian Medical Center, Department of Surgery, 600 West 168th Street, New York, NY 10032.

Present address: New England College of Optometry, Boston, MA 02115.

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