Myxoma viral serpin, Serp-1, a unique interceptor of coagulation and innate immune pathways

Kasinath Viswanathan; Liying Liu; Sepideh Vaziri; Erbin Dai; Jakob Richardson; Babajide Togonu-Bickersteth; Pracha Vatsya; Alexander Christov; Alexandra R. Lucas

doi:10.1160/TH05-07-0492

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(03): 499-510
DOI: 10.1160/TH05-07-0492

Wound Healing and Inflammation/Infection

Schattauer GmbH

Myxoma viral serpin, Serp-1, a unique interceptor of coagulation and innate immune pathways

Kasinath Viswanathan

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Liying Liu

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Sepideh Vaziri

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Erbin Dai

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Jakob Richardson

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Babajide Togonu-Bickersteth

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Pracha Vatsya

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Alexander Christov

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

,

Alexandra R. Lucas

¹Vascular Biology Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

²Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

³Division of Cardiology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

› Author Affiliations

Abstract

Summary

Serpins maintain haemostasis through regulation of serine proteinases in the thrombotic and thrombolytic pathways. Viruses encode serpins that can alter thrombotic and thrombolytic responses producing, in some cases, disseminated intravascular coagulation (DIC). However, it has not been precisely defined how viral serpins induce these profound responses. The rabbit myxoma viral serpin, Serp-1 inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA), plasmin and factor Xa in vitro and exhibits remarkable anti-inflammatory activity in various animal models. The effects of Serp-1 on activation of human platelets, endothelial cells, monocytes and T cells that mediate thrombosis and innate immune responses were therefore examined. We found that Serp-1 attenuated platelet and mononuclear cell adhesion to fibronectin and collagen. Serp-1 similarly inhibited monocyte migration into the peritoneum. Serp-1 inhibition of monocyte migration was lost in uPA receptor (uPAR) deficient mice. Serp-1 bound to the plasma membrane surface and altered uPA activation of endothelial cells (p=0.001), thrombin activation of platelets (p=0.021) and phorbol ester activation of endothelial (p=0.047), monocyte (p=0.011) and Jurkat T cells (p=0.012) as measured by intracellular calcium. Modulation of cellular activation was confirmed by membrane fluidity analysis. Microarray analysis of Serp-1 treated endothelial cells revealed alterations in Inositol 1,4,5-triphosphate receptor type II (ITPR2) a calcium-regulating gene. This study demonstrates the unique capacity ofa viral serpin, Serp-1 to modify adhesion, activation, gene expression and calcium homeostasis in a wide range of cells that regulate coagulation and inflammation. Endothelial cells potentially represent a pivotal regulatory point for Serp-1 anti-inflammatory activity.

Keywords

Serpin - adhesion - calcium - membrane fluidity - ITPR2

Full Text

References

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