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Infect Immun, August 1998, p. 3611-3617, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Role of Protegrins and Other Elastase-Activated Polypeptides in the Bactericidal Properties of Porcine Inflammatory Fluids

Jishu Shi and Tomas Ganz*

Will Rogers Institute Pulmonary Research Laboratory, Departments of Medicine and Pathology, School of Medicine, University of California at Los Angeles, Los Angeles, California 90095

Received 19 February 1998/Returned for modification 2 April 1998/Accepted 21 May 1998

The mammalian host response to infection includes the production and secretion of antimicrobial peptides from phagocytes and epithelial cells. Protegrins, a group of broadly microbicidal peptides isolated originally from porcine neutrophil lysates, were found to be stored as inactive proforms in porcine neutrophil granules but could be activated extracellularly by neutrophil elastase. We assessed the biological role of protegrins and other elastase-activated polypeptides in the microbicidal activity of neutrophil secretions and inflammatory fluids. When stimulated with phorbol myristate acetate (PMA), neutrophils generated stable microbicidal activity against both Escherichia coli and Listeria monocytogenes under normal-salt conditions and in the presence of 0 to 10% serum. The generation of these antimicrobial substances was dependent on neutrophil elastase, since it was inhibited by 1 mM N-methoxysuccinyl-Ala-Ala-Pro-Val chloromethyl ketone when it was present during activation, but not when this inhibitor was added afterwards. However, elastase-dependent activation of proprotegrins to protegrins in PMA-stimulated neutrophils was not inhibited by the presence of 1 to 2% serum. Porcine neutrophils also released antibacterial activity during phagocytosis of latex beads, and this too was dependent in large part on elastase-activated polypeptides, including protegrins. Moreover, protegrins were found at bactericidal concentrations in cell-free abscess fluid from naturally infected pigs. Taken together, these studies show that protegrins and other elastase-activated polypeptides are important stable antibacterial factors in porcine neutrophil secretions. The potential host defense role of elastase as an activating enzyme for the precursors of microbicidal peptides must be taken into account when therapeutic inhibitors of neutrophil elastase are evaluated for clinical use as anti-inflammatory agents.

* Corresponding author. Mailing address: Department of Medicine, CHS 37-055, 10833 Le Conte Ave., UCLA School of Medicine, Los Angeles, CA 90095. Phone: (310) 825-6112. Fax: (310) 206-8766. E-mail: tganz{at}ucla.edu.

Infect Immun, August 1998, p. 3611-3617, Vol. 66, No. 8
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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