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J. Biol. Chem., Vol. 280, Issue 41, 34832-34839, October 14, 2005

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Domain 5 of High Molecular Weight Kininogen Is Antibacterial^*

Emma Andersson Nordahl1, Victoria Rydengård, Matthias Mörgelin, and Artur Schmidtchen

From the Section of Dermatology and Venereology and Section of Clinical and Experimental Infectious Medicine, Department of Clinical Sciences, Lund, Biomedical Center, Lund University, Tornavägen 10, SE-221 84 Lund, Sweden

Antimicrobial peptides are important effectors of the innate immune system. These peptides belong to a multifunctional group of molecules that apart from their antibacterial activities also interact with mammalian cells and glycosaminoglycans and control chemotaxis, apoptosis, and angiogenesis. Here we demonstrate a novel antimicrobial activity of the heparin-binding and cell-binding domain 5 of high molecular weight kininogen. Antimicrobial epitopes of domain 5 were characterized by analysis of overlapping peptides. A peptide, HKH20 (His⁴⁷⁹-His⁴⁹⁸), efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and the Gram-positive Enterococcus faecalis. Fluorescence microscopy and electron microscopy demonstrated that HKH20 binds to and induces breaks in bacterial membranes. Furthermore, no discernible hemolysis or membrane-permeabilizing effects on eukaryotic cells were noted. Proteolytic degradation of high molecular weight kininogen by neutrophil-derived proteases as well as the metalloproteinase elastase from P. aeruginosa yielded fragments comprising HKH20 epitopes, indicating that kininogen-derived antibacterial peptides are released during proteolysis.

Received for publication, July 5, 2005 , and in revised form, August 8, 2005.

^* This work was supported by grants from the Swedish Research Council (project 13471), the Royal Physiographic Society in Lund, the Welander-Finsen, Söderberg, Groschinsky, Crafoord, Alfred Österlund, Lundgrens, Lions and Kock Foundations, DermaGen AB, and The Swedish Government Funds for Clinical Research (ALF). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Clinical Sciences, Lund, Biomedical Center B14, Tornavägen 10, SE-221 84 Lund, Sweden. Tel.: 46-46-120921; Fax: 46-46-157756; E-mail: emma.nordahl{at}med.lu.se.

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