Inactivation of human beta-defensins 2 and 3 by elastolytic cathepsins.
beta-Defensins are antimicrobial peptides that contribute to the innate immune responses of eukaryotes. At least three defensins, human beta-defensins 1, 2, and 3 (HBD-1, -2, and -3), are produced by epithelial cells lining the respiratory tract and are active toward Gram-positive (HBD-3) and Gram-negative (HBD-1, -2, and -3) bacteria. It has been postulated that the antimicrobial activity of defensins is compromised by changes in airway surface liquid composition in lungs of patients with cystic fibrosis (CF), therefore contributing to the bacterial colonization of the lung by Pseudomonas and other bacteria in CF. In this report we demonstrate that HBD-2 and HBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S. In addition, we show that all three cathepsins are present and active in CF bronchoalveolar lavage. Incubation of HBD-2 and -3 with CF bronchoalveolar lavage leads to their degradation, which can be completely (HBD-2) or partially (HBD-3) inhibited by a cathepsin inhibitor. These results suggest that beta-defensins are susceptible to degradation and inactivation by host proteases, which may be important in the regulation of beta-defensin activity. In chronic lung diseases associated with infection, overexpression of cathepsins may lead to increased degradation of HBD-2 and -3, thereby favoring bacterial infection and colonization.
Taggart
Clifford C
CC
Pulmonary Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Center, Beaumont Hospital, Dublin, Ireland. ctaggart@rcsi.i.e
Greene
Catherine M
CM
Smith
Stephen G
SG
Levine
Rodney L
RL
McCray
Paul B
PB
O'Neill
Shane
S
McElvaney
Noel G
NG
D000900:Anti-Bacterial Agents / Q000032:analysis / Q000037:antagonists & inhibitors / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D003550:Cystic Fibrosis / Q000201:enzymology / Q000382:microbiology; D004058:Diffusion; D004547:Elastic Tissue / Q000737:chemistry / Q000201:enzymology* / Q000382:microbiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000254:growth & development; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D023083:beta-Defensins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000900:Anti-Bacterial Agents; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D015842:Serine Proteinase Inhibitors; D023083:beta-Defensins; D002403:Cathepsins