Heparin-disaccharide affects T cells: inhibition of NF-kappaB activation, cell migration, and modulation of intracellular signaling.
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 alpha (TNF-alpha), interleukin (IL)-8, and IL-1beta] 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-kappaB activity and reduced the secretion of TNF-alpha and interferon-gamma (IFN-gamma) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1alpha)-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.
Hecht
Iris
I
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Hershkoviz
Rami
R
Shivtiel
Shoham
S
Lapidot
Tzvi
T
Cohen
Irun R
IR
Lider
Ofer
O
Cahalon
Liora
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D002633:Chemotaxis; D004187:Disaccharides / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D051418:Focal Adhesion Kinase 2; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004187:Disaccharides; D005353:Fibronectins; D051418:Focal Adhesion Kinase 2; D006493:Heparin; D006497:Heparan Sulfate; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse; C464536:heparin disaccharide; C496053:Ptk2b protein, mouse