Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2.
The expression of inducible antimicrobial peptides, such as human beta-defensin-2 (HBD-2) by epithelia, comprises a component of innate pulmonary defenses. We hypothesized that HBD-2 induction in airway epithelia is linked to pattern recognition receptors such as the Toll-like receptors (TLRs). We found that primary cultures of well-differentiated human airway epithelia express the mRNA for TLR-4, but little or no MD-2 mRNA, and display little HBD-2 expression in response to treatment with purified endotoxin +/- LPS binding protein (LBP) and soluble CD14. Expression of endogenous MD-2 by transduction of airway epithelial cells with an adenoviral vector encoding MD-2 or extracellular addition of recombinant MD-2 both increased the responses of airway epithelia to endotoxin + LBP and sCD14 by >100-fold, as measured by NF-kappaB-luciferase activity and HBD-2 mRNA expression. MD-2 mRNA could be induced in airway epithelia by exposure of these cells to specific bacterial or host products (e.g., killed Haemophilus influenzae, the P6 outer membrane protein from H. influenzae, or TNF-alpha + IFN-gamma). These findings suggest that MD-2, either coexpressed with TLR-4 or secreted when produced in excess of TLR-4 from neighboring cells, is required for airway epithelia to respond sensitively to endotoxin. The regulation of MD-2 expression in airway epithelia and pulmonary macrophages may serve as a means to modify endotoxin responsiveness in the airway.
Jia
Hong Peng
HP
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Kline
Joel N
JN
Penisten
Andrea
A
Apicella
Michael A
MA
Gioannini
Theresa L
TL
Weiss
Jerrold
J
McCray
Paul B
PB
D000954:Antigens, Surface / Q000235:genetics*; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology*; D005110:Extracellular Space / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology; D051218:Lymphocyte Antigen 96; D016676:Macrophages, Alveolar / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
D000954:Antigens, Surface; D004731:Endotoxins; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96