Published ahead of print on December 30, 2002, doi:10.1165/rcmb.2002-0191OC
Am. J. Respir. Cell Mol. Biol., Volume 28, Number 6, June 2003, 738-745
A more recent version of this article appeared on June 1, 2003
Submitted on October 1, 2002
Revised on December 27, 2002
The antimicrobial activity of the cathelicidin LL37 is inhibited by F-actin and restored by gelsolin
Daniel J Weiner1, Robert Bucki2, and Paul A Janmey2*
1 Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pa, USA,
2 Physiology, University Of Pennsylvania, Philadelphia, Pa, USA
* To whom correspondence should be addressed. E-mail: janmey{at}mail.med.upenn.edu.
Antimicrobial peptides are part of the innate host defense system, and inactivation of these peptides is implicated in airway infections in cystic fibrosis (CF). The sputum of CF patients contains anionic polyelectrolytes including F- actin and DNA not found in normal airway fluid. These anionic filaments aggregate to contribute to the altered viscoelastic properties of CF sputum. We hypothesized that the airway components stabilizing bundles of F-actin and DNA are in part cationic antimicrobial agents and that appropriate modification of diseased airway fluid of CF patients might dissociate these bundles and restore antimicrobial activity. We demonstrate that the human cathelicidin peptide LL37 forms bundles with F-actin and DNA, which are dissolved by gelsolin and DNAse, respectively. Coincident with bundle formation, antimicrobial activity of LL37 is inhibited by F-actin and DNA. Pseudomonas bacteria were killed by low concentrations of LL37, but killing was significantly reduced in the presence of F-actin. The actin filament fragmenting protein gelsolin restored bactericidal activity nearly completely. In a growth inhibition assay, the effects of F-actin were confirmed, and DNA was also shown to inhibit the activity of LL37. When added to CF sputum, gelsolin significantly reduced the growth of bacteria suggesting activation of endogenous antimicrobial factors. These findings may have therapeutic implications for treatments previously thought to alter only the viscoelastic properties of airway secretions and amplify the possible advantage of gelsolin in CF treatment.
This article has been cited by other articles:
|
|
|
|
 
R. Bucki, D. B. Namiot, Z. Namiot, P. B. Savage, and P. A. Janmey
Salivary mucins inhibit antibacterial activity of the cathelicidin-derived LL-37 peptide but not the cationic steroid CSA-13
J. Antimicrob. Chemother.,
August 1, 2008;
62(2):
329 - 335.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. J. Broughton-Head, J. Shur, M. P. Carroll, J. R. Smith, and J. K. Shute
Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis
Am J Physiol Lung Cell Mol Physiol,
November 1, 2007;
293(5):
L1240 - L1249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. K. Sanders, W. Xian, C. Guaqueta, M. J. Strohman, C. R. Vrasich, E. Luijten, and G. C. L. Wong
Control of electrostatic interactions between F-actin and genetically modified lysozyme in aqueous media
PNAS,
October 9, 2007;
104(41):
15994 - 15999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bucki, A. G. Sostarecz, F. J. Byfield, P. B. Savage, and P. A. Janmey
Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum
J. Antimicrob. Chemother.,
September 1, 2007;
60(3):
535 - 545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Hiemstra
Antimicrobial peptides in the real world: implications for cystic fibrosis
Eur. Respir. J.,
April 1, 2007;
29(4):
617 - 618.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bucki, F. J. Byfield, and P. A. Janmey
Release of the antimicrobial peptide LL-37 from DNA/F-actin bundles in cystic fibrosis sputum
Eur. Respir. J.,
April 1, 2007;
29(4):
624 - 632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. DiNubile
Plasma gelsolin: in search of its raison d'etre. Focus on "Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin"
Am J Physiol Cell Physiol,
April 1, 2007;
292(4):
C1240 - C1242.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Guaqueta, L. K. Sanders, G. C. L. Wong, and E. Luijten
The Effect of Salt on Self-Assembled Actin-Lysozyme Complexes
Biophys. J.,
June 15, 2006;
90(12):
4630 - 4638.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. E. Lau, D. M. E. Bowdish, C. Cosseau, R. E. W. Hancock, and D. J. Davidson
Apoptosis of Airway Epithelial Cells: Human Serum Sensitive Induction by the Cathelicidin LL-37
Am. J. Respir. Cell Mol. Biol.,
April 1, 2006;
34(4):
399 - 409.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Candiano, M. Bruschi, N. Pedemonte, E. Caci, S. Liberatori, L. Bini, C. Pellegrini, M. Vigano, B. J. O'Connor, T. H. Lee, et al.
Gelsolin Secretion in Interleukin-4-treated Bronchial Epithelia and in Asthmatic Airways
Am. J. Respir. Crit. Care Med.,
November 1, 2005;
172(9):
1090 - 1096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. X. Tang, Q. Wen, A. Bennett, B. Kim, C. A. Sheils, R. Bucki, and P. A. Janmey
Anionic poly(amino acid)s dissolve F-actin and DNA bundles, enhance DNase activity, and reduce the viscosity of cystic fibrosis sputum
Am J Physiol Lung Cell Mol Physiol,
October 1, 2005;
289(4):
L599 - L605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Gibson, J. L. Burns, and B. W. Ramsey
Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis
Am. J. Respir. Crit. Care Med.,
October 15, 2003;
168(8):
918 - 951.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2002 American Thoracic Society.
|
|
|
