Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation
Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation
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DOI：
10.1053/j.gastro.2004.11.053
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发表时间：
2005-03-01
期刊：
影响因子：
29.4
通讯作者：
Cominelli, F
中科院分区：
文献类型：
--
作者：
Bamias, G;Martin, C;Cominelli, F
背景与目的：严格的T（H）1极化被认为是克罗恩病肠道炎症发病机制的基础。在本研究中，我们检验了T（H）2细胞因子也可能参与SAMP 1/YitFc小鼠疾病发展的假设，SAMP 1/YitFc小鼠自发发展为末端回肠炎伴肛周表现。方法：采用实时荧光定量PCR技术检测细胞因子mRNA的表达。纯化固有层单核细胞（LP-MCs）并分析刺激的细胞因子分泌。通过使用特异性中和单克隆抗体（MAbs）来阻断干扰素（IFN）-γ或白细胞介素（IL）-4。从SAMP 1/YitFc肠系膜淋巴结（MLN）中纯化分泌CD 4 +/IL-4的淋巴细胞，并在转移至SCID受体后检测其诱导回肠炎的能力。结果如下：SAMP 1/YitFc小鼠回肠炎的起始是T（H）1介导的，因为IFN-γ和肿瘤坏死因子（TNF）的上调先于组织学损伤，而IFN-γ中和通过干扰淋巴细胞的扩增防止慢性炎症的发展（P < .005）。相反，慢性回肠炎的建立与IL-5（35倍）和IL-13（29倍）mRNA表达的显著增加（P <0.005）以及固有层淋巴细胞分泌的TH 2细胞因子的显著增加（与AKR对照组相比P <0.05）一致。IL-4阻断可降低IFN-γ mRNA的表达，并通过降低绒毛变形和活动性炎症的组织学指标，显著改善已建立的回肠炎的严重程度（P <0.05）。此外，IL-4增强了淋巴细胞的体外IFN-γ分泌，而分泌IL-4的CD 4+淋巴细胞足以过继转移回肠炎到SCID受体。结论：我们的研究结果表明，TH 1和TH 2途径介导克罗恩病样回肠炎，并建议联合T（H）1/T（H）2操作可能提供治疗克罗恩病的治疗优势。
Background & Aims: Strict T(H)1 polarization is believed to underlie the pathogenesis of intestinal inflammation in Crohn's disease. In the present study we tested the hypothesis that T(H)2 cytokines also may participate in disease development in SAMP1/YitFc mice that spontaneously develop terminal ileitis with perianal manifestations. Methods: Cytokine messenger RNA (mRNA) expression was studied by real-time polymerase chain reaction (PCR). Lamina propria mononuclear cells (LP-MCs) were purified and stimulated cytokine secretion was analyzed. Blockade of interferon (IFN)-gamma or interleukin (IL)-4 was performed by using specific neutralizing monoclonal antibodies (MAbs). CD4+/IL-4-secreting lymphocytes were purified from SAMP1/YitFc mesenteric lymph nodes (MLNs) and their ability to induce ileitis was tested after transfer to SCID recipients. Results: Initiation of ileitis in SAMP1/YitFc mice was T(H)1-mediated because up-regulation of IFN-gamma and tumor necrosis factor (TNF) preceded the histologic injury, whereas IFN-gamma neutralization prevented the development of chronic inflammation (P < .005) by interfering with the expansion of lymphocytes. In contrast, the establishment of chronic ileitis coincided with significant increases in IL-5 (35x) and IL-13 (29x) mRNA expression (P < .005), as well as in TH2 cytokine secretion by lamina propria lymphocytes (P < .05 vs. AKR controls). IL-4 blockade diminished IFN-gamma mRNA expression and significantly ameliorated the severity of established ileitis (P < .05) by decreasing the histologic indices for villous distortion and active inflammation. In addition, IL-4 augmented the in vitro IFN-gamma secretion by lymphocytes, whereas IL-4-secreting CD4+ lymphocytes were sufficient for adoptively transferring ileitis to SCID recipients. Conclusions: Our results indicate that both TH1 and TH2 pathways mediate Crohn's-like ileitis and suggest that combined T(H)1/T(H)2 manipulation may offer a therapeutic advantage for the treatment of Crohn's disease.