Bamias Giorgos, Martin Charles, Mishina Margarita, Ross William G, Rivera-Nieves Jesus, Marini Marco, Cominelli Fabio
Digestive Health Center of Excellence, University of Virginia Health Sciences Center, PO Box 800708, Charlottesville, Virginia 22908, USA.
Gastroenterology. 2005 Mar;128(3):654-66. doi: 10.1053/j.gastro.2004.11.053.
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 TH2 cytokines also may participate in disease development in SAMP1/YitFc mice that spontaneously develop terminal ileitis with perianal manifestations.
Cytokine messenger RNA (mRNA) expression was studied by real-time polymerase chain reaction (PCR). Lamina propria mononuclear cells (LPMCs) 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.
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 T H 2 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.
Our results indicate that both TH1 and TH2 pathways mediate Crohn's-like ileitis and suggest that combined TH1/TH2 manipulation may offer a therapeutic advantage for the treatment of Crohn's disease.
人们认为严格的Th1极化是克罗恩病肠道炎症发病机制的基础。在本研究中，我们检验了以下假设：Th2细胞因子也可能参与SAMP1/YitFc小鼠的疾病发展，该小鼠可自发发生伴有肛周表现的终末回肠炎。
通过实时聚合酶链反应（PCR）研究细胞因子信使核糖核酸（mRNA）表达。纯化固有层单核细胞（LPMC）并分析刺激后的细胞因子分泌。使用特异性中和单克隆抗体（MAb）阻断干扰素（IFN）-γ或白细胞介素（IL）-4。从SAMP1/YitFc肠系膜淋巴结（MLN）中纯化分泌IL-4的CD4+淋巴细胞，并将其转移至SCID受体后，检测其诱导回肠炎的能力。
SAMP1/YitFc小鼠回肠炎的起始由Th1介导，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阻止了慢性炎症的发展（P<.005）。相比之下，慢性回肠炎的形成与IL-5（35倍）和IL-13（29倍）mRNA表达的显著增加同时出现（P<.005），以及固有层淋巴细胞分泌的Th2细胞因子增加（与AKR对照组相比，P<.05）。IL-4阻断降低了IFN-γmRNA表达，并通过降低绒毛扭曲和活动性炎症的组织学指标，显著改善了已形成的回肠炎的严重程度（P<.05）。此外，IL-4增强了淋巴细胞体外IFN-γ的分泌，而分泌IL-4的CD4+淋巴细胞足以将回肠炎过继转移至SCID受体。
我们的结果表明，Th1和Th2途径均介导克罗恩样回肠炎，并提示联合Th1/Th2调控可能为克罗恩病的治疗提供治疗优势。
