This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2008-0408OCv1 42/4/424    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by John, G. Articles by Henke, M. O. PubMed PubMed Citation Articles by John, G. Articles by Henke, M. O.

TLR-4–Mediated Innate Immunity Is Reduced in Cystic Fibrosis Airway Cells

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

Correspondence and requests for reprints should be addressed to Markus O. Henke, M.D., Philipps-University Marburg, Department of Pulmonary Medicine, Baldingerstraße 1, 35043 Marburg, Germany. 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 (IL-8 and IL-6 secretion) in CF bronchial epithelial cell line CFBE41o- and its CF transmembrane ion condcutance regulator (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 with 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. Fluorescence-activated cell sorter analysis revealed significantly higher levels of TLR-4 surface expression in CFTR-corrected cells. In histologic lung sections of patients with CF, the TLR-4 expression in the bronchial epithelium was significantly reduced compared with 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: innate immunity • cystic fibrosis transmembrane ion conductance regulator • inflammation • Toll-like receptor • interleukin-8