Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Abstract

Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5% , P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-␣, CC chemokine ligand 3/macrophage inflammatory protein-1␣, and vascular cell adhesion molecule-1 , as determined by histological correlation between 0 and 15 days after colitis induction , TaqMan low-density array analysis , and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin , a functional analogue of the Sdc1 heparan sulfate chains , significantly reduced lethality of KO mice due to DSS-induced colitis , which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach. (Am J Pathol

Activated Syndecan-1 Shedding Contributes to Mice Colitis Induced by Dextran Sulfate Sodium

“…It is reported that apart from its anticoagulant effect, low-molecular-weight heparin is also characterized by its anti-inflammatory effect, which has been confirmed in human diseases and animal inflammatory models [25], and dysfunction of immune reaction resulting from T-cell activation disturbance is a common feature of the animals in these inflammatory models. The exact anti-inflammatory mechanisms of heparin have not yet been found.…”

Syndecan-1, a Cell Surface Proteoglycan, Negatively Regulates Initial Leukocyte Recruitment to the Brain across the Choroid Plexus in Murine Experimental Autoimmune Encephalomyelitis

“…Although syndecan-1 knockout (Sdc-1 2/2 ) mice show exacerbated disease symptoms in several inflammatory models (14), precisely why this is the case remains unclear. Most studies report enhanced immune cell infiltration in Sdc-1 2/2 mice, which has been correlated with enhanced extravasation from postcapillary venules because of effects ranging from modulation of integrin activity and interaction with cell adhesion molecules (14,15) to modulation of cytokine and chemokine gradients (16). Yet, the expression of syndecan-1 on endothelium and immune cells in vivo is difficult to detect, with the notable exception of B lymphocytes, which may be partially because of its dynamic regulation (9,(17)(18)(19).…”

Decorin Potentiates Interferon-γ Activity in a Model of Allergic Inflammation

“…Adhesion Assays-bEnd.3 cells were used for static lymphocyte adhesion assays, as described previously (26,49). Approximately 2 ϫ 10 4 endothelial cells/well were cultured in 96-well plates overnight, followed by treatment with 85 g/ml TNF-␣ to stimulate endothelial cells.…”