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Syndecan-4 on human peripheral blood lymphocytes and monocytes mediates effects of antithrombin on chemotaxis

Antithrombin inhibits chemokine-induced migration of neutrophils by activating heparan sulfate proteoglycan-dependent signaling. Whether antithrombin affects migration of other types of leukocytes is unknown. We investigated the effects of antithrombin on spontaneous and chemokine-triggered migration of lymphocytes and monocytes from human peripheral blood in modified Boyden chamber micropore filter assays. Lymphocyte and monocyte populations from human peripheral blood were purified using magnetic antibody cell sorting. Signaling mechanisms in antithrombin-dependent migration were studied by Western blot analyses of protein kinases and Rho activation, or were tested functionally by using signaling enzyme blockers. Expression of heparan sulfate proteoglycan core protein was studied by RT-PCR and flow cytometry. As antithrombins, the concentrate Kybernin®P from human plasma and a monoclonal antibody-purified preparation therefrom were used. Pretreatment of lymphocytes and monocytes with antithrombin inhibited chemotaxis toward optimal concentrations of interleukin-8 or Rantes at concentrations of antithrombin as low as 10 nU/ml; in the absence of the chemokines, direct exposure of cells to gradients of antithrombin stimulated migration. Effects of antithrombin were abolished by pretreating cells with heparinase-1, chondroitinase, sodium chlorate and anti-syndecan-4 antibodies. Expression of syndecan-4 mRNA and protein in monocytes and lymphocytes was demonstrated in RT-PCR and anti-syndecan-4 immunoreactivity assay, respectively. In the presence of pentasaccharide, antithrombin lost its activity on the cells. Antithrombin induced chondroitinase- and heparinase I-dependent phophorylation of protein kinase C-alpha and dissociation of Rho-GTPase. Data indicate that antithrombin directly inhibits chemokine-stimulated migration of monocytes and lymphocytes via effects of its heparin-binding site on cell surface syndecan-4 by activation of protein kinase C and Rho signaling.

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Kaneider, N., Reinisch, C., Dunzendorfer, S. et al. Syndecan-4 on human peripheral blood lymphocytes and monocytes mediates effects of antithrombin on chemotaxis. Crit Care 6 (Suppl 1), P120 (2002).

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