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Toll-Like Receptors in Normal and Cystic Fibrosis Airway Epithelial Cells

Departments of Pediatrics and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York; and Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio

Address correspondence to: Alice Prince, Department of Pediatrics and Pharmacology, College of Physicians and Surgeons, Columbia University, 416 Black Building, 650 W. 168th Street, New York, NY 10032. E-mail: asp7{at}columbia.edu

Toll-like receptors (TLRs) mediate cellular responses to diverse microbial ligands. The distribution and function of TLRs in airway cells were studied to identify which are available to signal the presence of inhaled pathogens and to establish if differences in TLR expression are associated with the increased proinflammatory responses seen in cystic fibrosis (CF). Isogenic, polarized CF and control bronchial epithelial cell lines, human airway cells in primary culture, and cftr null and wild-type mice were compared. TLRs 1–10, MD2, and MyD88 were expressed in CF and normal cells. Only TLR2 transcription was modestly increased in CF as compared with normal epithelial cells following bacterial stimulation. TLR2 was predominantly at the apical surface of airway cells and was mobilized to cell surface in response to bacteria. TLR4 was present in a more basolateral distribution in airway cells, but appeared to have a limited role in epithelial responses. Lipopolysaccharide failed to activate nuclear factor-B in these cells, and TLR2 dominant negative but not TLR4 dominant negative mutants inhibited activation by both Gram-negative and Gram-positive bacteria. Increased availability of TLR2 at the apical surfaces of CF epithelial cells is consistent with the increased proinflammatory responses seen in CF airways and suggests a selective participation of TLRs in the airway mucosa.

Abbreviations: cystic fibrosis, CF • transmembrane conductance regulator, CFTR • dominant-negative, DN • extracellular signal-related kinase, ERK • interleukin-8, IL-8 • IL-1 receptor–associated kinase, IRAK • lipopolysaccharide, LPS • mean fluorescence intensity, MFI • myeloid differentiation protein, MyD88 • nuclear factor-B, NF-B • phosphate-buffered saline, PBS • polymorphonuclear leukocytes, PMNs • reverse transcriptase–polymerase chain reaction, RT-PCR • toll-like receptor, TLR • TNF receptor–associated factor, TRAF

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