Alex Philip, Zachos Nicholas C, Nguyen Thuan, Gonzales Liberty, Chen Tian-E, Conklin Laurie S, Centola Michael, Li Xuhang
Div of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Inflamm Bowel Dis. 2009 Mar;15(3):341-52. doi: 10.1002/ibd.20753.
BACKGROUND: The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. METHODS: A novel approach of comprehensive serum multiplex cytokine profiling with biometric immunosandwich ELISA's was used to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Advanced multivariate discriminant functional analyses (DFA) was used to identify statistically interrelated sets of variables with the most significant power to discriminate among the groups. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa using Western blot analysis and fluorescent immunohistochemistry. RESULTS: Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNF-alpha, IL6, IL-17, and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNF-alpha, IL6, IL-17, and KC) in the chronic state. Moreover, DFA identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. CONCLUSIONS: Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD.
背景：炎症性肠病（IBD）中的细胞因子网络是一个复杂的动态系统，在调节黏膜固有免疫和适应性免疫反应中起重要作用。虽然已经进行了多项研究来评估小鼠IBD中的免疫调节谱，但这些研究仅限于相对较少的细胞因子，没有考虑到多种因素相互作用的依赖性，因此它们的细胞因子谱的诊断潜力尚无定论。 方法：采用一种新的生物计量免疫夹心ELISA综合血清多重细胞因子分析方法，描述在DSS和TNBS诱导的结肠炎急性和慢性小鼠模型中16种Th1、Th2、Th17细胞因子和趋化因子的调节情况。先进的多变量判别功能分析（DFA）用于识别具有最强判别组间能力的统计学相关变量集。还使用蛋白质印迹分析和荧光免疫组织化学在结肠黏膜局部验证全身观察到的多种细胞因子谱。 结果：确定了与疾病活动和病程显著相关的独特疾病特异性细胞因子谱。随着疾病变为慢性，TNBS结肠炎表现出Th1-Th17反应增强（IL-12和IL-17增加）。相比之下，DSS结肠炎从Th1-Th17介导的急性炎症（TNF-α、IL6、IL-17和KC增加）转变为慢性状态下主要由Th2介导的炎症反应（IL-4和IL-10增加，同时TNF-α、IL6、IL-17和KC减少）。此外，DFA确定了可充分用于区分未受影响的对照与疾病以及一种疾病类型与另一种疾病类型的判别性细胞因子谱。IL-6和IL-12对慢性结肠炎中与性别相关的疾病活动进行了分层。 结论：我们的研究为疾病免疫发病机制提供了见解，并说明了利用多重细胞因子谱和生物信息学作为IBD诊断工具的巨大潜力。
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