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Published ahead of print on June 5, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2008-0408OC
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Submitted on October 22, 2008
Accepted on June 3, 2009

Toll-like Receptor (TLR)-4 Mediated Innate Immunity is Reduced in Cystic Fibrosis Airway Cells

Gerrit John1, Ali Ö Yildirim2, Bruce K. Rubin3, Dieter C Gruenert4, and Markus O Henke5*

1 Department of Pulmonary Medicine, Philipps-University Marburg, Marburg, Germany, 2 Department of Clinical Chemistry and Molecular Diagnostics, Philipps-University Marburg, Marburg, Germany, 3 Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States, 4 Department of Laboratory Medicine, California Pacific Medical Center Research Institute, University of California, San Francisco, California, United States, 5 Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany

* To whom correspondence should be addressed. E-mail: markus.henke{at}staff.uni-marburg.de.

Airway epithelial cells contribute to the inflammatory response of the lung and their innate immune response is primarily mediated via Toll-like receptor (TLR) signaling. Cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. We investigated the TLR-4 expression and the inflammatory profile (Interleukin (IL)-8 and IL-6 secretion) in CF bronchial epithelial cell line CFBE41o- and its CFTR corrected counterpart grown under air-liquid interface conditions after stimulation with lipopolysaccharide (LPS) from Gram-negative bacteria. In CFTR corrected cells, IL-8 and IL-6 secretions were constitutively activated but significantly increased after LPS stimulation compared to CFBE41o-. Blocking TLR-4 by a specific antibody significantly inhibited IL-8 secretion only in CFTR corrected cells. Transfection with specific siRNA directed against TLR-4 mRNA significantly reduced the response to LPS in both cell lines. FACS analysis revealed significantly higher levels of TLR-4 surface expression in CFTR corrected cells. In histological lung sections of CF patients the TLR-4 expression in the bronchial epithelium was significantly reduced compared to healthy control subjects. In CF the loss of CFTR function appears to decrease innate immune responses, possibly by altering the expression of TLR-4 on airway epithelial cells. This may contribute to chronic bacterial infection of CF airways.
Key words: CFTR • Innate immunity • Inflammation • Toll-like receptor • Interleukin-8






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