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1 Department of Pediatrics, University of Iowa, Iowa City, IA, USA
2 Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
3 Department of Microbiology, University of Iowa, Iowa City, IA, USA; Department of The Inflammation Program, University of Iowa, Iowa City, IA, USA
4 Department of Biochemistry, University of Iowa, Iowa City, IA, USA; Department of The Inflammation Program, University of Iowa, Iowa City, IA, USA
5 Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; Department of The Inflammation Program, University of Iowa, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: paul-mccray{at}uiowa.edu.
The expression of inducible antimicrobial peptides such as human 
-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 TLR4 but little or no MD-2 mRNA and display little HBD-2 expression in response to treatment with purified endotoxin +/- LBP and sCD14. 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-
B-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 H. influenzae, the P6 outer membrane protein from H. influenzae, or TNF-
+ INF-
). These findings suggest that
MD-2, either co-expressed with TLR4 or secreted when produced in excess of TLR4 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.
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