IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis
IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis
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DOI：
10.4049/jimmunol.178.9.5957
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Monteleone, Giovanni
中科院分区：
文献类型：
--
作者：
Caruso, Roberta;Fina, Daniele;Monteleone, Giovanni
幽门螺杆菌（Helicobacter pylori，Hp）感染与胃炎症和溃疡有关。幽门螺杆菌感染的组织损伤的途径是复杂的，但有证据表明，T细胞衍生的细胞因子增强基质金属蛋白酶（MMP）的合成，有助于粘膜溃疡和上皮损伤。在这项研究中，我们研究了T细胞因子IL-21在Hp感染的胃粘膜中的作用，并评估IL-21是否调节胃上皮细胞MMP的产生。我们发现IL-21在胃粘膜中组成性表达，并且与正常患者和疾病对照相比，在Hp感染患者的活检标本和纯化的粘膜CD 3（+）T细胞中更丰富。我们还表明，IL-21 R表达的原代胃上皮细胞，以及胃上皮细胞系AGS和MKN 28。一致地，AGS细胞通过增加MMP-2和MMP-9的产生而不是MMP-1、MMP-3、MMP-7或MMP的组织抑制剂来响应IL-21。导致MMP产生的信号通路的分析揭示IL-21增强NF-κ B而非MAPK活化，并且NF-κ B活化的抑制降低IL-21诱导的MMP-2和MMP-9产生。最后，我们表明，治疗幽门螺杆菌感染的胃外植体与抗IL-21减少上皮细胞来源的MMP-2和MMP-9的生产。这些数据表明，IL-21在Hp感染的胃粘膜中过表达，它可能有助于增加上皮明胶酶的产生。
Helicobacter pylori (Hp) infection is associated with gastric inflammation and ulceration. The pathways of tissue damage in Hp-infected subjects are complex, but evidence indicates that T cell-derived cytokines enhance the synthesis of matrix metalloproteinases (MMP) that contribute to mucosal ulceration and epithelial damage. In this study, we have examined the role of the T cell cytokine IL-21 in Hp-infected gastric mucosa and evaluated whether IL-21 regulates MMP production by gastric epithelial cells. We show that IL-21 is constitutively expressed in gastric mucosa and is more abundant in biopsy specimens and purified mucosal CD3(+) T cells from Hp-infected patients compared with normal patients and disease controls. We also demonstrate that IL-21R is expressed by primary gastric epithelial cells, as well as by the gastric epithelial cell lines AGS and MKN28. Consistently, AGS cells respond to IL-21 by increasing production of MMP-2 and MMP-9, but not MMP-1, MMP-3, MMP-7, or tissue inhibitors of MMP. Analysis of signaling pathways leading to MMP production reveals that IL-21 enhances NF-KB but not MAPK activation, and inhibition of NF-kappa B activation reduces IL-21-induced MMP-2 and MMP-9 production. Finally, we show that treatment of Hp-infected gastric explants with anti-IL-21 reduces epithelial cell-derived MMP-2 and MMP-9 production. These data indicate that IL-21 is overexpressed in Hp-infected gastric mucosa where it could contribute to increased epithelial gelatinase production.