title: Cell surface-anchored syndecan-1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis.
abstract: Syndecan-1 (SDC1), with a variable ectodomain carrying heparan sulphate (HS) chains between different Syndecans, participates in many steps of inflammatory responses. In the process of proteolysis, the HS chains of the complete extracellular domain can be shed from the cell surface, by which they can mediate most of SDC1's function. However, the exact impact on SDC1 which anchored on the cell surface has not been clearly reported. In our study, we established the models by transfection with the cleavable resistant SDC1 mutant plasmid, in which SDC1 shedding can be suppressed during stimulation. Role of membrane SDC1 in inflammatory pathway, pro-inflammatory cytokine secretion as well as neutrophil transmigration, and how suppressing its shedding will benefit colitis were further investigated. We found that the patients suffered ulcerative colitis had high serum SDC1 levels,presented with increased levels of P65, tumour necrosis factor alpha (TNF-α) and IL-1β and higher circulating neutrophils. NF-κB pathway was activated, and secretion of TNF-α, interleukin-1beta (IL-1β), IL-6 and IL-8 were increased upon lipopolysaccharide stimuli in intestinal epithelial cells. Syndecan-1, via its anchored ectodomain, significantly lessened these up-regulation extents. It also functioned in inhibiting transmigration of neutrophils by decreasing CXCL-1 secretion. Moreover, SDC1 ameliorated colitis activity and improved histological disturbances of colon in mice. Taken together, we conclude that suppression of SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation and neutrophil transmigration by inactivating key inflammatory regulators NF-κB, and down-regulating pro-inflammatory cytokine expressions. These indicated that compenstion and shedding suppression of cytomembrane SDC1 might be the optional therapy for intestinal inflammation.
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Yan
authors: Y
authors: Zhang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.|Department of Radiation Oncology and Cyberknife Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Zhongqiu
authors: Z
authors: Wang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.|Department of Gastroenterology, Liuzhou Worker's Hospital, Liuzhou, China.
authors: Jun
authors: J
authors: Liu
authors: Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors: Shaoheng
authors: S
authors: Zhang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Jiaxi
authors: J
authors: Fei
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Jing
authors: J
authors: Li
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Ting
authors: T
authors: Zhang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Jide
authors: J
authors: Wang
authors: Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Pyong W
authors: PW
authors: Park
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors: Ye
authors: Y
authors: Chen
mesh_terms: D000328:Adult; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D053668:Syndecan-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; C508241:SDC1 protein, human; D053668:Syndecan-1
keywords: NF-κB pathway; ectodomain shedding; intestinal inflammation; neutrophil transmigration; pro-inflammatory cytokine; syndecan-1