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Published online before print March 12, 2004

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(Journal of Leukocyte Biology. 2004;75:1139-1146.)
© 2004 by Society for Leukocyte Biology

Heparin-disaccharide affects T cells: inhibition of NF-B activation, cell migration, and modulation of intracellular signaling

Iris Hecht^*, Rami Hershkoviz, Shoham Shivtiel^*, Tzvi Lapidot^*, Irun R. Cohen^*, Ofer Lider^*,1 and Liora Cahalon^*

^* Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and
The Sakler Faculty of Medicine, Tel-Aviv University, Israel

¹ Correspondence: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: ofer.lider{at}weizmann.ac.il

We previously reported that disaccharides (DS), generated by enzymatic degradation of heparin or heparan sulfate, inhibit T cell-mediated immune reactions in rodents and regulate cytokine [tumor necrosis factor (TNF-), interleukin (IL)-8, and IL-1ß] secretion by T cells, macrophages, or intestinal epithelial cells. Here, we investigated the effects of a trisulfated heparin DS (3S-DS) on two aspects of T cell function: secretion of proinflammatory cytokines and migration to an inflamed site. 3S-DS down-regulated nuclear factor-B activity and reduced the secretion of TNF- and interferon- (IFN-) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1)-dependent migration in vitro and in vivo and decreased CXCL12-induced T cell adhesion to the extracellular matrix glycoprotein, fibronectin (FN). This inhibition was accompanied by attenuation of CXCL12-induced Pyk2 phosphorylation but did not involve internalization of the CXCL12 receptor, CXCR4, or phosphorylation of extracellular-regulated kinase. Despite inhibiting CXCL12-induced adhesion, 3S-DS, on its own, induced T cell adhesion to FN, which was accompanied by phosphorylation of Pyk2. A monosulfated DS showed no effect. Taken together, these data provide evidence that 3S-DS can regulate inflammation by inducing and modulating T cell-signaling events, desensitizing CXCR4, and modulating T cell receptor-induced responses.

Key Words: chemokines • CXCL12 • extracellular matrix • TNF- • IFN-

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