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Neutrophil-Derived Proteinase 3 Induces Kallikrein-Independent Release of a Novel Vasoactive Kinin^1,2

Robin Kahn^*, Thomas Hellmark, L. M. Fredrik Leeb-Lundberg, Nasrin Akbari^*, Mihail Todiras, Tor Olofsson^¶, Jörgen Wieslander^||, Anders Christensson^#, Kerstin Westman, Michael Bader, Werner Müller-Esterl^** and Diana Karpman^3,*

^* Department of Pediatrics, Clinical Sciences Lund, Department of Nephrology, Clinical Sciences Lund, Unit of Drug Target Discovery, Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden; Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany; ^¶ Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; ^|| Wieslab, Lund, Sweden; ^# Department of Nephrology and Transplantation, Clinical Sciences Malmö, Lund University, Lund, Sweden; and ^** Institute of Biochemistry II, University Hospital, Frankfurt, Germany

The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH₂-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and ₁-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B₁ receptors, but did not bind to B₂ receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B₂ receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B₁ and B₂ receptors as demonstrated using wild-type and B₁ overexpressing rats as well as wild-type and B₂ receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was presented in part in poster form at the 13th Congress of the International Pediatric Nephrology Association, August 29 to September 2, 2004, Adelaide, Australia, and the 2nd International Conference on Exploring the Future of Vascular and Inflammatory Mediators, Kinin 2007, May 30 to June 2, 2007, Berlin, Germany.

² This study was supported by grants from the Swedish Research Council (K2007-64X-14008-07-3), the fund for Renal Research, Crown Princess Lovisa’s Society for Child Care, the Sven Jerring Foundation, Konung Gustaf V:s 80-årsfond, Fanny Ekdahl’s Foundation (all to D.K.) and Queen Silvia’s Jubilee fond (to R.K.) and the Swedish Research Council (grant 15057; to L.M.F.L.L.). Diana Karpman is the recipient of a clinical-experimental research fellowship from the Royal Swedish Academy of Sciences.

³ Address correspondence and reprint requests to Dr. Diana Karpman, Department of Pediatrics, Lund University, 22185 Lund, Sweden. E-mail address: Diana.Karpman{at}med.lu.se

⁴ Abbreviations used in this paper: HK, high-molecular weight kininogen; PR3, proteinase 3; ₁-AT, ₁-antitrypsin; ANCA, anti-neutrophil cytoplasmic Abs; KLKs, kallikreins; EACA, -amino-n-caproic acid; GEMSA, 2-guanidinoethylmercaptosuccinic acid; ESI, electrospray ionization; PI, phosphoinositide.

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