Toll-like receptors in normal and cystic fibrosis airway epithelial cells.
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-kappaB 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.
Muir
Amanda
A
Department of Pediatrics and Pharmacology, College of Physicians and Surgeons, Columbia University, 416 Black Building, 650 W. 168th Street, New York, NY 10032, USA.
Soong
Grace
G
Sokol
Sach
S
Reddy
Bharat
B
Gomez
Marisa I
MI
Van Heeckeren
Anna
A
Prince
Alice
A
D000818:Animals; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
C505032:CFTR protein, human; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside