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

在这项研究中，我们试图阐明人胸腺基质淋巴生成素（TSLP）在炎症性肠病中的病理生理作用，我们得到了以下结果。(1)经TSLP激活的树突状细胞（Dendritic cells, DCs）表达于粘膜淋巴样组织上皮细胞中，可诱导自体T_H2记忆细胞强劲扩增。由tslp激活的dc介导的T_H2记忆细胞的维持和稳态扩张需要自肽-主要组织相容性复合体、共刺激分子，特别是OX40和OX40配体之间的相互作用。除了通过DC激活间接作用于t细胞增殖外，TSLP还直接促进CD4^+ t细胞增殖。此外，T细胞受体刺激激活的CD8^+ T细胞表达TSLP受体，TSLP直接促进活化的CD8^+细胞的增殖。(2)尽管幽门螺杆菌在胃中定植并诱导慢性活动性胃炎，但在更多的小肠中Peyer's斑块在幽门螺杆菌特异性的局部和全身体液免疫和细胞介导免疫中发挥重要作用，包括幽门螺杆菌诱导的胃炎的发生。此外，幽门螺杆菌触发人胃上皮细胞产生TSLP和dc吸引的趋化因子，上皮细胞条件的dc表达高水平的共刺激分子，并触发幼稚CD4 T细胞产生高水平的炎性Th2细胞因子。(3) TNF-a触发人结肠上皮细胞产生TSLP， IL-4增强TNF-a诱导的TSLP在结肠上皮细胞中的表达。髓系DCs对TSLP和TLR3配体(L)的联合反应上调功能性TSLP受体和TLR3的表达。虽然单用TSLP不能诱导DCs产生IL-23，但单用TLR3-L可诱导DCs产生IL-23，而TSLP和TLR3-L联合可诱导DCs进一步产生IL-23。由TSLP和TLR3-L联合激活的dc诱导幼稚CDC T细胞产生IL-17和IL-22，并产生高水平的Th2细胞因子和TNF-α。少

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