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

Journal of Leukocyte Biology

Iris Hecht²  Liora Cahalon²  Rami Hershkoviz¹  Irun R. Cohen²  Tzvi Lapidot²  Shoham Shivtiel²  Ofer Lider² 

[1] The Sakler Faculty of Medicine, Tel-Aviv University, Israel The Sakler Faculty of Medicine, Tel-Aviv University, Israel The Sakler Faculty of Medicine, Tel-Aviv University, Israel;Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and

关键词: chemokines;    CXCL12;    extracellular matrix;    TNF-α;    IFN-γ;   

DOI  :  10.1189/jlb.1203659

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 α (TNF-α), interleukin (IL)-8, and IL-1β] 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-κB activity and reduced the secretion of TNF-α and interferon-γ (IFN-γ) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1α)-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.

【 授权许可】

Unknown