Open Access Open Badges Research article

Modulation of granulocyte-endothelium interactions by antileukoproteinase: inhibition of anti-type II collagen antibody-induced leukocyte attachment to the synovial endothelium

Bettina Sehnert1, Philip Gierer23, Saleh Ibrahim4, Anja Kühl2, Reinhard Voll5, Kutty Selva Nandakumar6, Rikard Holmdahl6, Rupert Hallmann7, Brigitte Vollmar2 and Harald Burkhardt18*

Author Affiliations

1 Department of Internal Medicine III and Institute of Clinical Immunology at the Friedrich-Alexander-University of Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany

2 Department of Experimental Surgery, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

3 Department of Trauma and Reconstructive Surgery, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

4 Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

5 IZKF Research Group N2, Nikolaus-Fiebiger Center, and Department of Internal Medicine III, Friedrich-Alexander-University of Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany

6 Section for Medical Inflammation Research, BMC I11, Lund University, Sweden

7 Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstrasse 15, 48149 Münster, Germany

8 Current address: Division of Rheumatology, Johann Wolfgang Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

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Arthritis Research & Therapy 2006, 8:R95  doi:10.1186/ar1973

Published: 15 June 2006


Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have anti-inflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.