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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0808506

Received for publication August 27, 2008.
Revised October 31, 2008.
Accepted for publication October 31, 2008.

Article

Myxoma viral serpin, Serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B

Kasinath Viswanathan *, Jakob Richardson *{dagger}, Babajide Togonu-Bickersteth *{dagger}, Erbin Dai *{ddagger}, Liying Liu *{ddagger}, Pracha Vatsya *{dagger}, Yun-ming Sun {dagger}{sect}, Jeff Yu *, Ganesh Munuswamy-Ramunujam *{dagger}{ddagger}||, Henry Baker {ddagger}, and Alexandra R. Lucas *{dagger}{ddagger}||@

*Vascular Biology Research Group, Robarts Research Institute, and {dagger}Departments of Microbiology & Immunology and Medicine, University of Western Ontario, London, Ontario, Canada; Departments of ||Cardiovascular Medicine and {ddagger}Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida, USA; and {sect}Viron Therapeutics, Inc., London, Ontario, Canada

@ To whom correspondence should be addressed. E-mail: alexandra.lucas{at}medicine.ufl.edu.


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Abstract

Serp-1 is a secreted myxomaviral serine protease inhibitor (serpin) with proven, highly effective, anti-inflammatory defensive activity during host cell infection, as well as potent immunomodulatory activity in a wide range of animal disease models. Serp-1 binds urokinase-type plasminogen activator (uPA) and tissue-type PA, plasmin, and factor Xa, requiring uPA receptor (uPAR) for anti-inflammatory activity. To define Serp-1-mediated effects on inflammatory cell activation, we examined the association of Serp-1 with monocytes and T cells, effects on cellular migration, and the role of uPAR-linked integrins and actin-binding proteins in Serp-1 cellular responses. Our results show that Serp-1 associates directly with activated monocytes and T lymphocytes, in part through interaction with uPAR (P<0.001). Serp-1, but not mammalian serpin PA inhibitor-1 (PAI-1), attenuated cellular adhesion to the extracellular matrix. Serp-1 and PAI-1 reduced human monocyte and T cell adhesion (P<0.001) and migration across endothelial monolayers in vitro (P<0.001) and into mouse ascites in vivo (P<0.001). Serp-1 and an inactive Serp-1 mutant Serp-1(SAA) bound equally to human monocytes and T cells, but a highly proinflammatory mutant, Serp-1(Ala6), bound less well to monocytes. Serp-1 treatment of monocytes increased expression of filamin B actin-binding protein and reduced CD18 ({beta}-integrin) expression (P<0.001) in a uPAR-dependent response. Filamin colocalized and coimmunoprecipitated with uPAR, and short interference RNA knock-down of filamin blocked Serp-1 inhibition of monocyte adhesion. We report here that the highly potent, anti-inflammatory activity of Serp-1 is mediated through modification of uPAR-linked {beta}-integrin and filamin in monocytes, identifying this interaction as a central regulatory axis for inflammation.

Key Words: virus • thrombolysis • inflammation • macrophage