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Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule.

Kalle, Martina LU ; Papareddy, Praveen LU ; Kasetty, Gopinath LU ; Tollefsen, Douglas M; Malmsten, Martin; Mörgelin, Matthias LU and Schmidtchen, Artur LU (2013) In Journal of Immunology 190(12). p.6303-6310
Abstract
The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals... (More)
The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
190
issue
12
pages
6303 - 6310
publisher
American Association of Immunologists
external identifiers
  • wos:000320373700044
  • pmid:23656734
  • scopus:84879072604
ISSN
1550-6606
DOI
10.4049/jimmunol.1203030
language
English
LU publication?
yes
id
6e98f245-1355-4e68-8e49-984c11e25055 (old id 3804760)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23656734?dopt=Abstract
date added to LUP
2013-06-06 16:00:01
date last changed
2019-07-02 01:33:23
@article{6e98f245-1355-4e68-8e49-984c11e25055,
  abstract     = {The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.},
  author       = {Kalle, Martina and Papareddy, Praveen and Kasetty, Gopinath and Tollefsen, Douglas M and Malmsten, Martin and Mörgelin, Matthias and Schmidtchen, Artur},
  issn         = {1550-6606},
  language     = {eng},
  number       = {12},
  pages        = {6303--6310},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1203030},
  volume       = {190},
  year         = {2013},
}