C-terminal peptides of tissue factor pathway inhibitor are novel host defense molecules.
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.
Papareddy
Praveen
P
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
Kalle
Martina
M
Kasetty
Gopinath
G
Mörgelin
Matthias
M
Rydengård
Victoria
V
Albiger
Barbara
B
Lundqvist
Katarina
K
Malmsten
Martin
M
Schmidtchen
Artur
A
D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002417:Cattle; D003167:Complement Activation; D015926:Complement C3a / Q000096:biosynthesis; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis; D005260:Female; D005658:Fungi / Q000187:drug effects; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007871:Leg Ulcer / Q000378:metabolism; D008074:Lipoproteins / Q000737:chemistry*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012867:Skin / Q000293:injuries / Q000378:metabolism
D000890:Anti-Infective Agents; D015938:Complement Membrane Attack Complex; D008074:Lipoproteins; D010446:Peptide Fragments; C051928:lipoprotein-associated coagulation inhibitor; D015926:Complement C3a