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Elucidation of pathaphysiological roles of human thymic stromal lymphopoietin (TSLP) in inflammatory bowel diseases

阐明人胸腺基质淋巴细胞生成素（TSLP）在炎症性肠病中的病理生理学作用

基本信息

批准号：
18590679
负责人：
WATANABE Norihiko
金额：
$ 2.44万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

In this study, we tried to elucidate pathophysiological roles of human thymic stromal lymphopoietin (TSLP) in inflammatory bowel diseases and we obtained the following results. (1) Dendritic cells (DCs) activated by TSLP, expressed in the epithelial cells of mucosal lymphoid tissues, can induce a robust expansion of autologous T_H2 memory cells. The maintenance and homeostatic expansion of T_H2 memory cells mediated by TSLP-activated DCs require the self peptide-major histocompatibility complex, costimulatory molecules, and particularly, the interactions between OX40 and OX40 ligand. In addition to indirectly action on T-cell proliferation through DC activation, TSLP directly promotes CD4^+ T-cell proliferation. Moreover, CD8^+ T cells activated by T cell receptor stimulation expresse TSLP receptor, and that TSLP directly enhances proliferation of activated CD8^+ cells. (2) Although Helicobacter bacteria colonize in the stomach and induce chronic active gastritis, Peyer's patches in th … More e small intestine have an important role in Helicobacter-specific local and systemic humoral and cell-mediated immunity, including the development of Helicobacter-induced gastritis. In addition, Helicobacter triggers human gastric epithelial cells to produce TSLP and DC-attracting chemokines and epithelial cell-conditioned DCs expresses high levels of costimulatory molecules and triggers naive CD4 T cells to produce high levels of the inflammatory Th2 cytokines. (3) TNF-a triggers human colonic epithelial cells to produce TSLP and IL-4 enhances TNF-a-inducing TSLP expression in colonic epithelial cells. Myeloid DCs responded to a combination of TSLP and TLR3-ligand(L) to upregulate expression of functional TSLP receptor and TLR3. Although TSLP alone did not induce IL-23 production by DCs, TLR3-L alone primed DCs for production of IL-23, and a combination of TSLP and TLR3-L primed DCs for further production of IL-23. DCs activated by a combination of TSLP and TLR3-L primed naive CDC T cells to produce IL-17 and IL-22, together with high levels of Th2 cytokines and TNF-α. Less

本研究试图阐明人胸腺基质淋巴细胞生成素（TSLP）在炎症性肠病中的病理生理作用。(1)TSLP激活的DC在粘膜淋巴组织的上皮细胞中表达，可以诱导自体TH 2记忆细胞的大量扩增。TSLP激活的DC介导的T_H2记忆细胞的维持和稳态扩增需要自身肽-主要组织相容性复合物、共刺激分子，特别是OX 40和OX 40配体之间的相互作用。除了通过DC活化间接作用于T细胞增殖外，TSLP还直接促进CD 4 ^+ T细胞增殖。此外，通过T细胞受体刺激活化的CD 8 ^+ T细胞表达TSLP受体，并且TSLP直接促进活化的CD 8 ^+细胞的增殖。(2)虽然幽门螺杆菌在胃中定植并引起慢性活动性胃炎，但胃粘膜中的派尔集合淋巴结 ...更多信息小肠在螺杆菌特异性局部和全身体液和细胞介导的免疫中具有重要作用，包括螺杆菌诱导的胃炎的发展。此外，螺杆菌触发人胃上皮细胞产生TSLP和DC吸引趋化因子，上皮细胞条件DC表达高水平的共刺激分子，并触发初始CD 4 T细胞产生高水平的炎性Th 2细胞因子。(3)TNF-α触发人结肠上皮细胞产生TSLP，IL-4增强结肠上皮细胞中TNF-α诱导的TSLP表达。髓样DC对TSLP和TLR 3-配体（L）的组合应答以上调功能性TSLP受体和TLR 3的表达。虽然单独的TSLP不诱导DC产生IL-23，但是单独的TLR 3-L引发DC产生IL-23，并且TSLP和TLR 3-L的组合引发DC进一步产生IL-23。由TSLP和TLR 3-L的组合激活的DC致敏的幼稚CDC T细胞产生IL-17和IL-22，以及高水平的Th 2细胞因子和TNF-α。少