Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice.
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-alpha, CC chemokine ligand 3/macrophage inflammatory protein-1alpha, 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.
Floer
Martin
M
Department of Medicine B, Albert Schweitzer Strasse 33, D-48149 Muenster, Germany. martinfloer@web.de
Götte
Martin
M
Wild
Martin K
MK
Heidemann
Jan
J
Gassar
Ezeddin Salem
ES
Domschke
Wolfram
W
Kiesel
Ludwig
L
Luegering
Andreas
A
Kucharzik
Torsten
T
D000818:Animals; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate; D017984:Enoxaparin / Q000627:therapeutic use*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D053668:Syndecan-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D017984:Enoxaparin; D034741:RNA, Small Interfering; D053668:Syndecan-1; D016222:Fibroblast Growth Factor 2; D018799:Intercellular Adhesion Molecule-1; D016264:Dextran Sulfate