Cell surface-anchored syndecan-1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis.
Cell surface-anchored syndecan-1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis.
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细胞表面锚定的 syndecan-1 改善溃疡性结肠炎中的肠道炎症和中性粒细胞迁移
DOI：
10.1111/jcmm.12934
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发表时间：
2017-01
影响因子：
5.3
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang Z;Liu J;Zhang S;Fei J;Li J;Zhang T;Wang J;Park PW;Chen Y
Syndecan-1（SDC 1）具有在不同Syndecan之间携带硫酸乙酰肝素（HS）链的可变胞外域，参与炎症反应的许多步骤。在蛋白水解过程中，完整的胞外结构域的HS链可以从细胞表面脱落，从而它们可以介导SDC 1的大部分功能。然而，对锚定在细胞表面的SDC 1的确切影响尚未明确报道。在我们的研究中，我们建立了模型，通过转染可切割的抗性SDC 1突变质粒，其中SDC 1脱落可以抑制在刺激过程中。进一步研究了膜SDC 1在炎症途径、促炎细胞因子分泌以及中性粒细胞迁移中的作用，以及抑制其脱落将如何有益于结肠炎。我们发现，溃疡性结肠炎患者血清SDC 1水平较高，表现为P65、肿瘤坏死因子α（TNF-α）和IL-1β水平升高以及循环中性粒细胞增多。肠上皮细胞经脂多糖刺激后，NF-κB通路被激活，TNF-α、白细胞介素-1 β（IL-1β）、IL-6和IL-8分泌增加。Syndecan-1通过其锚定的胞外域显著降低了这些上调程度。它还通过减少CXCL-1分泌来抑制中性粒细胞的迁移。此外，SDC 1改善了小鼠结肠炎活动并改善了结肠的组织学紊乱。综上所述，我们得出结论，抑制SDC 1从肠上皮细胞脱落可通过灭活关键炎症调节因子NF-κB和下调促炎细胞因子表达来减轻肠道炎症和中性粒细胞迁移的严重程度。提示SDC 1对细胞膜代偿和脱落的抑制作用可能是治疗肠道炎症的一种选择。
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.
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影响因子：
5.4
作者：
Manon-Jensen, Tina;Multhaupt, Hinke A. B.;Couchman, John R.
通讯作者：
Couchman, John R.
影响因子：
4.8
作者：
Elenius, V;Götte, M;Bernfield, M
通讯作者：
Bernfield, M
影响因子：
15.9
作者：
Bode, Lars;Salvestrini, Camilla;Freeze, Hudson H.
通讯作者：
Freeze, Hudson H.
溃疡性结肠炎。
DOI：
10.1016/s0140-6736(16)32126-2
发表时间：
2017-04-29
期刊：
Lancet (London, England)
影响因子：
--
作者：
Ungaro R;Mehandru S;Allen PB;Peyrin-Biroulet L;Colombel JF
通讯作者：
Colombel JF
DOI：
10.4049/jimmunol.1001293
发表时间：
2010-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Brazil JC;Lee WY;Kolegraff KN;Nusrat A;Parkos CA;Louis NA
通讯作者：
Louis NA