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 (β-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.
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Myxoma viral serpin, Serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B
Viswanathan, Kasinath; Richardson, Jakob; Togonu-Bickersteth, Babajide; Dai, Erbin; Liu, Liying; Vatsya, Pracha; Sun, Yun-ming; Yu, Jeff; Munuswamy-Ramanujam, Ganesh; Baker, Henry; Lucas, Alexandra R.
Follow Journal of Leukocyte Biology
, Volume 85 (3): 418
Fed of American Socs for Experimental Biology – Mar 1, 2009
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