Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3804760
- author
- Kalle, Martina LU ; Papareddy, Praveen LU ; Kasetty, Gopinath LU ; Tollefsen, Douglas M ; Malmsten, Martin LU ; Mörgelin, Matthias LU and Schmidtchen, Artur LU
- organization
- publishing date
- 2013
- 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
- 2016-04-01 11:08:54
- date last changed
- 2022-01-26 05:50:19
@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}}, doi = {{10.4049/jimmunol.1203030}}, volume = {{190}}, year = {{2013}}, }