MIP-3α neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice
MIP-3α neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice
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DOI：
10.1152/ajpgi.00409.2006
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发表时间：
2007-05-01
影响因子：
4.5
通讯作者：
Keates, Andrew C.
中科院分区：
文献类型：
--
作者：
Katchar, Kianoosh;Kelly, Ciaran P.;Keates, Andrew C.
人类炎症性肠病，特别是克罗恩病的一个特征是存在活化的CD 4（+）T细胞。最近，我们发现结肠上皮细胞产生巨噬细胞炎性蛋白（MIP）-3 α，一种CD 4 T细胞导向的趋化因子，在炎症性肠病中升高。然而，在肠道炎症过程中MIP-3 α产生的功能相关性知之甚少。本研究的目的是确定在鼠2，4，6-三硝基苯磺酸（TNBS）诱导的结肠炎期间MIP-3 α的产生是否增加，并检查在该模型中施用抗MIP-3 α中和单克隆抗体的效果。我们发现，TNBS的管理显着增加结肠MIP-3 α蛋白水平在Balb/ c小鼠。与此一致，在TNBS处理的动物中也观察到携带CCR 6的固有层CD 4（+）和CD 8（+）T细胞的数量显著增加。用抗MIP-3 α中和性单克隆抗体治疗小鼠可显著降低TNBS介导的结肠重量/长度比增加、粘膜溃疡、组织学损伤和髓过氧化物酶活性。TNBS介导的携带CCR 6的固有层T细胞数量的增加也被抗MIP-3 α中和单克隆抗体处理显著降低。总之，我们的发现表明MIP-3 α生物活性的阻断可以显著减少TNBS介导的结肠损伤和T细胞募集，表明该趋化因子在肠道炎症的病理生理学中的作用。
A characteristic feature of human inflammatory bowel disease, particularly Crohn's disease, is the presence of activated CD4(+) T cells. Recently, we have shown that colonic epithelial cell production of macrophage inflammatory protein ( MIP)-3 alpha, a CD4 T cell- directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3 alpha production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3 alpha production is increased during murine 2,4,6- trinitrobenzene sulfonic acid ( TNBS)- induced colitis and to examine the effect of anti-MIP-3 alpha neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3 alpha protein levels in Balb/ c mice. Consistent with this, a marked increase in the number of CCR6-bearing lamina propria CD4(+) and CD8(+) T cells was also observed in TNBS-treated animals. Treatment of mice with an anti-MIP-3 alpha neutralizing monoclonal antibody significantly reduced TNBS-mediated increases in colonic weight-to-length ratio, mucosal ulceration, histological damage, and myeloperoxidase activity. TNBS- mediated increases in the number of CCR6-bearing lamina propria T cells were also substantially reduced by anti-MIP-3 alpha neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3 alpha bioactivity can significantly reduce TNBS- mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.