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Myxoma viral serpin, Serp‐1, inhibits human monocyte adhesion through regulation of actin‐binding protein filamin B
Author(s) -
Viswanathan Kasinath,
Richardson Jakob,
TogonuBickersteth Babajide,
Dai Erbin,
Liu Liying,
Vatsya Pracha,
Sun Yunming,
Yu Jeff,
MunuswamyRamanujam Ganesh,
Baker Henry,
Lucas Alexandra R.
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0808506
Subject(s) - biology , serpin , urokinase receptor , microbiology and biotechnology , monocyte , filamin , cell adhesion , integrin , receptor , immunology , cell , biochemistry , cytoskeleton , gene
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.