Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2013 May 10

PMID 23656734

Citations 18

Authors

Martina Kalle

Praveen Papareddy

Gopinath Kasetty

Douglas M Tollefsen

Martin Malmsten

Matthias Morgelin

Artur Schmidtchen

Affiliations

Soon will be listed here.

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.

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References

Garcia-Montoya I, Cendon T, Arevalo-Gallegos S, Rascon-Cruz Q . Lactoferrin a multiple bioactive protein: an overview. Biochim Biophys Acta. 2011; 1820(3):226-36. PMC: 7127262. DOI: 10.1016/j.bbagen.2011.06.018. View

Villa P, Aznar J, Vaya A, Espana F, Ferrando F, Mira Y . Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis. Thromb Haemost. 1999; 82(3):1011-4. View

Hoffman M, Pratt C, Brown R, Church F . Heparin cofactor II-proteinase reaction products exhibit neutrophil chemoattractant activity. Blood. 1989; 73(6):1682-5. View

Papareddy P, Rydengard V, Pasupuleti M, Walse B, Morgelin M, Chalupka A . Proteolysis of human thrombin generates novel host defense peptides. PLoS Pathog. 2010; 6(4):e1000857. PMC: 2858699. DOI: 10.1371/journal.ppat.1000857. View

Tollefsen D . Vascular dermatan sulfate and heparin cofactor II. Prog Mol Biol Transl Sci. 2010; 93:351-72. DOI: 10.1016/S1877-1173(10)93015-9. View

Kario K, Matsuo T, Kodama K, Katayama S, Kobayashi H . Preferential consumption of heparin cofactor II in disseminated intravascular coagulation associated with acute promyelocytic leukemia. Thromb Res. 1992; 66(4):435-44. DOI: 10.1016/0049-3848(92)90292-i. View

Rossi E, Duboscq C, Kordich L . [Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role]. Medicina (B Aires). 1999; 59(1):95-104. View

Maekawa H, Sato H, Tollefsen D . Thrombin inhibition by HCII in the presence of elastase-cleaved HCII and thrombin-HCII complex. Thromb Res. 2001; 100(5):443-51. DOI: 10.1016/s0049-3848(00)00350-9. View

Choi K, Chow L, Mookherjee N . Cationic host defence peptides: multifaceted role in immune modulation and inflammation. J Innate Immun. 2012; 4(4):361-70. PMC: 6741489. DOI: 10.1159/000336630. View

10.

Malmstrom E, Morgelin M, Malmsten M, Johansson L, Norrby-Teglund A, Shannon O . Protein C inhibitor--a novel antimicrobial agent. PLoS Pathog. 2009; 5(12):e1000698. PMC: 2788422. DOI: 10.1371/journal.ppat.1000698. View

11.

Tollefsen D, Pestka C . Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood. 1985; 66(4):769-74. View

12.

Perlmutter D, Glover G, Rivetna M, Schasteen C, Fallon R . Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. Proc Natl Acad Sci U S A. 1990; 87(10):3753-7. PMC: 53981. DOI: 10.1073/pnas.87.10.3753. View

13.

Papareddy P, Kalle M, Kasetty G, Morgelin M, Rydengard V, Albiger B . C-terminal peptides of tissue factor pathway inhibitor are novel host defense molecules. J Biol Chem. 2010; 285(36):28387-98. PMC: 2934703. DOI: 10.1074/jbc.M110.127019. View

14.

Dawson D, Volpert O, Gillis P, Crawford S, Xu H, BENEDICT W . Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999; 285(5425):245-8. DOI: 10.1126/science.285.5425.245. View

15.

Davis 3rd A, Lu F, Mejia P . C1 inhibitor, a multi-functional serine protease inhibitor. Thromb Haemost. 2010; 104(5):886-93. DOI: 10.1160/TH10-01-0073. View

16.

PEMBERTON P, Stein P, Pepys M, Potter J, Carrell R . Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988; 336(6196):257-8. DOI: 10.1038/336257a0. View

17.

Bodenstine T, Seftor R, Khalkhali-Ellis Z, Seftor E, Pemberton P, Hendrix M . Maspin: molecular mechanisms and therapeutic implications. Cancer Metastasis Rev. 2012; 31(3-4):529-51. DOI: 10.1007/s10555-012-9361-0. View

18.

Loof T, Schmidt O, Herwald H, Theopold U . Coagulation systems of invertebrates and vertebrates and their roles in innate immunity: the same side of two coins?. J Innate Immun. 2010; 3(1):34-40. DOI: 10.1159/000321641. View

19.

Rau J, Beaulieu L, Huntington J, Church F . Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 2007; 5 Suppl 1:102-15. PMC: 2670448. DOI: 10.1111/j.1538-7836.2007.02516.x. View

20.

Schmidtchen A . Degradation of antiproteinases, complement and fibronectin in chronic leg ulcers. Acta Derm Venereol. 2000; 80(3):179-84. DOI: 10.1080/000155500750042925. View