Novel actions of thrombin-derived host defense peptides

Finja Hansen

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

97 Nedladdningar (Pure)


Thrombin-derived C-terminal peptides (TCPs) constitute a novel class of immunomodulatory host defense peptides, generated during infection and inflammation. Previous investigations have shown that TCPs of 2-3 kDa inhibit pro-inflammatory immune responses in vitro and in vivo, but their mode of action remained unclear. Paper I shows that the prototypic TCP GKY25 binds to LPS, thereby preventing TLR4 dimerization and subsequent activation of downstream signaling pathways in monocytes and macrophages. Furthermore, we found that GKY25 blocks TLR4- and TLR2-induced NF-κB/AP-1 activation in response to several other microbial-derived agonists as well. Whereas the first publication explains the effect of GKY25 on cell activation by purified bacterial components, the effect of GKY25 on whole bacteria and their interaction with immune cells remained unclear. In paper II we show the presence of TCPs in chronic and acute wound fluids, and that GKY25 binds to Gram-negative bacteria in the extra- and intracellular environment and reduces the pro-inflammatory immune response of monocytes/macrophages while preserving their important phagocytic function. During the investigations of the modes of action of TCPs, we observed that GKY25 is internalized in monocytes and macrophages. However, the exact uptake mechanism remained unknown. Therefore, in paper III we show that TCPs of 2-3 kDa are differently internalized by clathrin-dependent and -independent endocytosis pathways in monocytes and macrophages, depending on the type of cells, the length of the peptide, and the presence of LPS or bacteria. Internalized GKY25 was transported to lysosomes, where it remained detectable for up to 10 h. Finally, paper IV describes a TCP of about 11 kDa, which forms amorphous aggregates in the presence of LPS and Gram-negative bacteria, leading to scavenging, phagocytosis, and killing. Taken together, herein we show that the multifunctional TCPs play a physiological role during infection and inflammation, and have therapeutic potential by modulating multiple interactions involving bacteria, endotoxins, and
inflammatory cell responses.
Tilldelande institution
  • Institutionen för kliniska vetenskaper, Lund
  • van Der Plas, Mariena, handledare
  • Schmidtchen, Artur, Biträdande handledare
  • Herwald, Heiko, Biträdande handledare
Tilldelningsdatum2018 juni 8
ISBN (tryckt)978-91-7619-655-7
StatusPublished - 2018

Bibliografisk information

Defence details
Date: 2018-06-08
Time: 13:00
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund
External reviewer(s)
Name: Harder, Jürgen
Title: Prof. Dr. rer. nat.
Affiliation: University Medical Center Schleswig-Holstein, Kiel University
ISSN: 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2018:89

Ämnesklassifikation (UKÄ)

  • Dermatologi och venereologi


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