Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease phenotype
Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease phenotype
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DOI：
10.1111/j.1572-0241.2005.00361.x
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发表时间：
2006-01-01
影响因子：
9.8
通讯作者：
Lohse, P
中科院分区：
文献类型：
--
作者：
Brand, S;Hofbauer, K;Lohse, P
背景：fractalkine 受体 CX3CR1 已被证明参与炎症和免疫反应。最近，报道了 CX3CR1 的两种多态性（V249I 和 T280M）。 目的：我们的目的是分析 fractalkine 表达以及 CX3CR1 多态性在克罗恩病 (CD) 中的作用。方法：我们测定了用促炎细胞因子刺激后肠上皮细胞 (IEC) 系 SW480 以及发炎 (n = 14) 和炎症 (n = 14) 中 fractalkine mRNA 的表达。通过定量 PCR 检测非炎症 (n = 14) CD 病变。通过限制性片段长度多态性分析，对 206 名 CD 患者和 211 名无关对照的基因组 DNA 进行了 CX3CR1 基因中两个单核苷酸多态性的分析，这两个单核苷酸多态性导致了 V249I 和 T280M 取代。 结果：所有促炎刺激物（TNF-α、IL-1β、LPS）均显着增加 IEC 中 fractalkine mRNA 的表达。与未发炎的结肠粘膜相比，CD 患者发炎病变中的 fractalkine mRNA 表达也显着增加 (p = 0.02)。肠道 fractalkine mRNA 水平与 IL-8 mRNA 表达水平高度相关 (r = 0.931)。然而，CD患者和对照组之间的V249I和T280M基因型频率没有差异。在CD组中，V249I多态性为杂合性33.0%，纯合性为8.3%，T280M多态性为杂合性23.3%，纯合性为4.4%。所有 T280M 纯合子均被诊断为肠狭窄（与野生型和杂合子携带者相比，p = 0.03），并且与野生型和杂合子基因型患者相比，回结肠受累的频率明显更高（p = 0.01）。这些关联与 CARD15 基因型状态无关。结论：趋化因子 fractalkine 的表达受到促炎细胞因子的上调，并在发炎的 CD 病变中增强。 CX3CR1 T280M 多态性似乎影响 CD 表型和定位。
BACKGROUND: The fractalkine receptor CX3CR1 has been shown to be involved in inflammation and immune response. Recently, two polymorphisms of CX3CR1 (V249I and T280M) were reported.AIMS: Our aim was to analyze fractalkine expression and the role of CX3CR1 polymorphisms in Crohn's disease (CD).METHODS: We determined fractalkine mRNA expression in the intestinal epithelial cell (IEC) line SW480 after stimulation with proinflammatory cytokines as well as in inflamed (n = 14) and noninflamed (n = 14) CD lesions by quantitative PCR. By restriction fragment length polymorphism analysis, genomic DNA from 206 patients with CD and 211 unrelated controls was analyzed for the two single nucleotide polymorphisms in the CX3CR1 gene, which result in the V249I and T280M substitutions.RESULTS: All proinflammatory stimuli (TNF-alpha, IL-1 beta, LPS) significantly increased fractalkine mRNA expression in IEC. There was also a significant increase in fractalkine mRNA expression in inflamed lesions of CD patients when compared to noninflamed colonic mucosa (p= 0.02). Intestinal fractalkine mRNA levels correlated highly with IL-8 mRNA expression levels (r = 0.931). However, there was no difference in the V249I and T280M genotype frequencies between CD patients and the control group. In the CD group, 33.0% were heterozygous and 8.3% homozygous for the V249I polymorphism, while 23.3% were heterozygous and 4.4% homozygous for the T280M polymorphism. All T280M homozygotes were diagnosed of intestinal stenosis (p= 0.03 vs wildtype and heterozygous carriers) and had significantly more often ileocolonic involvement more often than patients with wildtype and heterozygous genotypes (p= 0.01). These associations were independent of the CARD15 genotype status.CONCLUSIONS: The expression of the chemokine fractalkine is upregulated by proinflammatory cytokines and enhanced in inflamed CD lesions. The CX3CR1 T280M polymorphism appears to influence CD phenotype and localization.