TY - JOUR
T1 - Myxoma viral serpin, serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B
AU - Viswanathan, Kasinath
AU - Richardson, Jakob
AU - Togonu-Bickersteth, Babajide
AU - Dai, Erbin
AU - Liu, Liying
AU - Vatsya, Pracha
AU - Sun, Yun Ming
AU - Yu, Jeff
AU - Munuswamy-Ramanujam, Ganesh
AU - Baker, Henry
AU - Lucas, Alexandra R.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2009/3/1
Y1 - 2009/3/1
N2 - Serp-1 is a secreted myxoma viral 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 the 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(Ala 6), bound less well to monocytes. Serp-1 treatment of monocytes increased expression of filamin B actin-binding protein and reduced CD18 (P-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 β-integrin and filamin in monocytes, identifying this interaction as a central regulatory axis for inflammation.
AB - Serp-1 is a secreted myxoma viral 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 the 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(Ala 6), bound less well to monocytes. Serp-1 treatment of monocytes increased expression of filamin B actin-binding protein and reduced CD18 (P-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 β-integrin and filamin in monocytes, identifying this interaction as a central regulatory axis for inflammation.
KW - Inflammation
KW - Macrophage
KW - Thrombolysis
KW - Virus
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UR - http://www.scopus.com/inward/citedby.url?scp=61449133139&partnerID=8YFLogxK
U2 - 10.1189/jlb.0808506
DO - 10.1189/jlb.0808506
M3 - Article
C2 - 19052145
AN - SCOPUS:61449133139
SN - 0741-5400
VL - 85
SP - 418
EP - 426
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 3
ER -