Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation
Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation
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DOI：
10.3748/wjg.14.7075
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发表时间：
2008-12-14
影响因子：
4.3
通讯作者：
Linard, Christine
中科院分区：
文献类型：
--
作者：
Gremy, Olivier;Benderitter, Marc;Linard, Christine
目的：探讨免疫失衡是否是慢性放射性肠炎发生、发展的原因。我们分析了结肠直肠分割照射后早期和6个月的Th 1/Th 2免疫应答特征。大鼠结肠直肠γ射线分次照射模型的建立（4-戈伊剂量，每周3次），旨在研究累积剂量对炎症介质的影响（细胞因子和趋化因子）和免疫反应（Th 1/Th 2曲线和免疫抑制介质IL-10）在急性（早期）反应期间和分次照射结束后6个月（慢性反应）。在累积剂量为16戈伊和36戈伊的1天后，以及累积剂量为52戈伊的1天、3天和26周后进行分析。结果：在不造成组织学损伤的情况下，分次辐射诱导了IL-1 β、TNF α、MCP-1和iNOS在远侧结肠粘膜中的表达升高。此时，通过Th 2特异性转录因子加塔-3和趋化因子受体CCR 4的表达以及通过在整个照射方案中抑制Th 1细胞因子IFN γ/IP-10来确认Th 2分布。6个月后，尽管iNOS和MCP-1水平降低了2倍，但Th 2特征持续存在，如Th 1转录因子T-bet、趋化因子受体CCXCR 3和IFN γ/STAT 1通路的表达降低了50%所示。在同一时间点，免疫抑制性IL-10/STAT 3途径，已知调节Th 1/Th 2平衡，在辐射大鼠中表达，与对照组相比，其水平约为一半。结论：大肠照射可诱导Th 2极化、IL-10/STAT 3通路激活缺陷和SOCS 3过表达。这些变化反过来又会维持长期存在的免疫失衡。(C)2008年，WJG出版社。All rights reserved.
AIM: To investigate if an immune imbalance may account for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation.METHODS: A rat model of fractionated colorectal gamma-irradiation (4-Gy fractions, 3 fractions per week) was designed to investigate the effects of cumulative dose on inflammatory mediators (cytokines and chemokines) and immune response (Th1/Th2 profile and immunosuppressive mediator IL-10) during acute (early) response and 6 mo after the end of fractionated irradiation (chronic response). Analyses were performed 1 d after the cumulative doses of 16 Gy and 36 Gy and 1 d, 3 d, and 26 wk after the cumulative dose of 52 Gy.RESULTS: Without causing histological damage, fractionated radiation induced elevated expression of IL-1 beta, TNF alpha, MCP-1, and iNOS in distal colonic mucosa during the early post-irradiation phase. At that time, a Th2 profile was confirmed by expression of both the Th2-specific transcription factor GATA-3 and the chemokine receptor CCR4 and by suppression of the Th1 cytokine IFN gamma/IP-10 throughout the irradiation protocol. After 6 mo, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% reduction in the expression of the Th1 transcription factor T-bet, the chemokine receptor CCXCR3, and the IFN gamma/ STAT1 pathway. At the same time-point, the immunosuppressive IL-10/STAT3 pathway, known to regulate the Th1/Th2 balance, was expressed, in irradiated rats, at approximately half its level as compared to controls. This suppression was associated with an overexpression of SOCS3, which inhibits the feedback of the Th1 polarization and regulates IL-10 production.CONCLUSION: Colorectal irradiation induces Th2 polarization, defective IL-10/STAT3 pathway activation and SOCS3 overexpression. These changes, in turn, maintain a immunological imbalance that persists in the long term. (C) 2008 The WJG Press. All rights reserved.