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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/L531    most recent 90292.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Illek, B. Articles by Machen, T. E. Search for Related Content PubMed PubMed Citation Articles by Illek, B. Articles by Machen, T. E.

Flagellin-stimulated Cl^– secretion and innate immune responses in airway epithelia: role for p38

¹Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California; and ²National Eye Institute, National Institutes of Health, Bethesda, Maryland

Submitted 30 April 2008 ; accepted in final form 20 July 2008

Activation of an innate immune response in airway epithelia by the human pathogen Pseudomonas aeruginosa requires bacterial expression of flagellin. Addition of flagellin (10^–7 M) to airway epithelial cell monolayers (Calu-3, airway serous cell-like) increased Cl^– secretion (I_Cl) beginning after 3–10 min, reaching a plateau after 20–45 min at I_Cl = 15–50 µA/cm². Similar, although 10-fold smaller, responses were observed in well-differentiated bronchial epithelial cultures. Flagellin stimulated I_Cl in the presence of maximally stimulating doses of the purinergic agonist ATP, but had no effects following forskolin. IL-1β (produced by both epithelia and neutrophils during infections) stimulated I_Cl similar to flagellin. Flagellin-, IL-1β-, ATP-, and forskolin-stimulated I_Cl were inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) blockers GlyH101, CFTRinh172, and glibenclamide. Neither flagellin nor IL-1β altered transepithelial fluxes of membrane-impermeant dextran (10 kDa) or lucifer yellow (mol wt = 457), but both activated p38, NF-B, and IL-8 secretion. Blockers of p38 (SB-202190 and SB-203580) reduced flagellin- and IL-1β-stimulated I_Cl by 33–50% but had smaller effects on IL-8 and NF-B. It is concluded that: 1) flagellin and IL-1β activated p38, NF-B, IL-8, and CFTR-dependent anion secretion without altering tight junction permeability; 2) p38 played a role in regulating I_Cl and IL-8 but not NF-B; and 3) p38 was more important in flagellin- than IL-1β-stimulated responses. During P. aeruginosa infections, flagellin and IL-1β are expected to increase CFTR-dependent ion and fluid flow into and bacterial clearance from the airways. In cystic fibrosis, the secretory response would be absent, but activation of p38, NF-B, and IL-8 would persist.

cystic fibrosis transmembrane conductance regulator; inflammation; airway epithelial secretion; interleukin-1β; Pseudomonas aeruginosa