Abstract
Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C terminus, also modulate cell surface, heparin, and 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 "classic" human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GGLIKTKRKRKKQRVKIAYEEIFVKNM (GGL27), was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classic 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.
Highlights
To control our microbial flora, humans and virtually all life forms are armored with rapidly acting host defense systems based on various antimicrobial peptides [1,2,3]
To elucidate whether C-terminal peptides of Tissue factor pathway inhibitor (TFPI) possess antimicrobial activity, we investigated the effects of defined regions of TFPI previously reported to be generated by proteolytic action, as well as the peptide LIK
The key findings in this study are the identification of a dual antimicrobial activity of C-terminal TFPI peptides, based on direct and complement-mediated bactericidal effects, the demonstration of an anti-endotoxic effect, combined with the identification of TFPI in skin, its up-regulation during wounding, and presence in wounds
Summary
To control our microbial flora, humans and virtually all life forms are armored with rapidly acting host defense systems based on various antimicrobial peptides [1,2,3]. 2 ϫ 106 cfu/ml bacteria were incubated in 50 l, at 37 °C for 2 h with the C-terminal TFPI-derived peptides GGL27, TKR22, or LIK17 at the indicated concentrations.
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