C-terminal peptides of tissue-factor pathway inhibitor are novel host defense molecules.

Research output: Contribution to journalArticle

Abstract

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C-terminus, also modulate cell surface-, heparin-, lipopolysaccharide interactions as well as participate in growth inhibition. Here we show that C-terminal TFPI peptide sequences are antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungi Candida albicans and Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen for the "classical" human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GLIKTKRKRKKQRVKIAYEEIFVKNM, was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classical pathway of complement activation. Furthermore, GGL27 displayed anti-endotoxic effects in vitro and in vivo in a mouse model of LPS-shock. Importantly, TFPI was found to be expressed in the basal layers of normal epidermis, and was markedly up-regulated in acute skin wounds as well as wound edges of chronic leg ulcers. Furthermore, C-terminal fragments of TFPI were associated with bacteria present in human chronic leg ulcers. These findings suggest a new role for TFPI in cutaneous defense against infections.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Dermatology and Venereal Diseases
  • Infectious Medicine
Original languageEnglish
Pages (from-to)28387-28398
JournalJournal of Biological Chemistry
Volume285
Issue number36
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes

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