The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis
The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis
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DOI：
10.1093/intimm/dxh284
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Kakimi, K
中科院分区：
文献类型：
--
作者：
Tokuyama, H;Ueha, S;Kakimi, K
趋化因子受体CCR 2、CCR 5和CXCR 3参与巨噬细胞和T细胞介导的免疫应答的调节以及这些细胞的迁移和活化。为了确定这些趋化因子受体的阻断是否调节肠道炎症，我们在此研究了非肽趋化因子受体拮抗剂TAK-779（N，N-二甲基-N-[4-[2-（4-甲基苯基）-6，7-二氢-5H-苯并环庚烯-8-基]羰基]氨基]苄基]-四氢-2H-吡喃-4-氯化铵）在葡聚糖硫酸钠（DSS）诱导的实验性结肠炎小鼠中的作用。C57 BL/6小鼠在给予或不给予TAK-779的情况下，通过饮用水喂食5% DSS长达7天。通过临床体征和组织学检查评估结肠炎症的严重程度。通过免疫组织化学分析炎性细胞向粘膜的浸润，并通过逆转录-PCR定量组织中细胞因子和趋化因子mRNA的表达。在DSS诱导的结肠炎期间，单核细胞/巨噬细胞向结肠粘膜的募集和促炎细胞因子的诱导与肠道炎症的严重程度相关。TAK-779给药动物的临床体征和组织病理学特征发生延迟。TAK-779给药小鼠中CCR 2、CCR 5和CXCR 3 mRNA的表达受到抑制。与这些结果一致，在TAK-779给药小鼠中，单核细胞/巨噬细胞向固有层的浸润几乎完全受到抑制，结肠IL-1 β和IL-6的表达显著降低。CCR 2、CCR 5和CXCR 3的阻断通过抑制炎性细胞募集到粘膜中来预防鼠实验性结肠炎。因此，趋化因子及其受体可能是治疗炎症性肠病的治疗靶点。
Chemokine receptors CCR2, CCR5 and CXCR3 are involved in the regulation of macrophage- and T cell-mediated immune responses and in the migration and activation of these cells. In order to determine whether blockade of these chemokine receptors modulates intestinal inflammation, we investigated here the effect of a non-peptide chemokine receptor antagonist, TAK-779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-tetrahydro-2H-pyran-4-aminium chloride), in mice with dextran sodium sulfate (DSS)-induced experimental colitis. C57BL/6 mice were fed 5% DSS in their drinking water for up to 7 days with or without the administration of TAK-779. The severity of inflammation in the colon was assessed by clinical signs and histological examination. Infiltration of inflammatory cells into the mucosa was analyzed by immunohistochemistry, and the expression of cytokine and chemokine mRNAs in tissues was quantitated by reverse transcription-PCR. During DSS-induced colitis, the recruitment of monocytes/macrophages into the colonic mucosa and the induction of proinflammatory cytokines correlated with the severity of intestinal inflammation. The onset of clinical signs and histopathologic features were delayed in animals treated with TAK-779. The expression of CCR2, CCR5 and CXCR3 mRNAs was inhibited in the TAK-779-treated mice. Consistent with these results, infiltration of monocytes/macrophages into the lamina propria was almost completely inhibited and the expression of colonic IL-1 beta and IL-6 was significantly decreased in the TAK-779-treated mice. The blockade of CCR2, CCR5 and CXCR3 prevents murine experimental colitis by inhibiting the recruitment of inflammatory cells into the mucosa. Therefore, chemokines and their receptors may be therapeutic targets for the treatment of inflammatory bowel disease.