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Role of intraperitoneal cell-traffic and TGF superfamily members in inflammatory bowel diseases

腹膜内细胞运输和 TGF 超家族成员在炎症性肠病中的作用

基本信息

批准号：
17590693
负责人：
DOHI Taeko
金额：
$ 2.24万
依托单位：
Research Institute, International Medical Center of Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The aim of this study was to clarify the mechanism of inflammatory cell infiltration in mouse model of inflammatory bowel disease by focusing the cell trafficking and immune system in the peritoneal cavity. Initially we found great loss of peritoneal macrophages in peritoneal exudate after induction of colitis and increased number of immature granulocyte-type cells. We investigated the specific recruitment of peritoneal macrophages (PMФs) by adoptive transfer of fluorescence-labeled peritoneal macrophages, and their expression of chemokine receptors. PMФs aggregated at the site of injured serosal side of the colon. The chemokine receptor CCR8 was upregulated in the aggregating PMФs when compared with naive PMФs. The upregulation of CCR8 was also observed in PMФs, but not in bone marrow-derived macrophages, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMФs and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. LPS-challenged PMФs also produced a TGF-superfamily member activin. Cell aggregation involving PMФand PMCs was induced in vitro in the presence of CCL1. CCR8 gene deficient mice or mice treated with anti-CCL1 neutralizing antibody exhibited significantly reduced serosal macrophage accumulation. Our study now establishes a unique autocrine activation system in PMФ and the mechanism for recruitment of PMФs together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity. Here we found an efficient defense mechanism as a specific function of peritoneal macrophages when inflammatory or surgical stress reaches to the deep inside of the body.

本研究的目的是通过关注腹腔内的细胞运输和免疫系统来阐明炎症性肠病小鼠模型中炎症细胞浸润的机制。最初，我们发现诱导结肠炎后腹腔渗出液中的腹腔巨噬细胞大量丢失，未成熟粒细胞型细胞数量增加。我们研究了通过过继转移荧光标记的腹腔巨噬细胞的特异性募集，及其趋化因子受体的表达。PM颗粒在损伤侧结肠部位聚集。趋化因子受体CCR 8在聚集性PM中表达上调，与幼稚PM相比。在用包括细菌组分和细胞因子的炎性刺激剂处理的PM巨噬细胞中也观察到CCR 8的上调，但在骨髓来源的巨噬细胞中未观察到。重要的是，CCL 1，CCR 8的配体，一种炎症刺激后的PMs和腹膜间皮细胞（PMC）的产物，是CCR 8表达的有效增强剂。受到LPS攻击的PMФs还产生了TGF超家族成员激活素。在CCL 1存在下，体外诱导涉及PM β和PMC的细胞聚集。CCR 8基因缺陷小鼠或用抗CCL 1中和抗体处理的小鼠表现出显著降低的血清巨噬细胞蓄积。我们的研究建立了一个独特的自分泌激活系统在PM ESTA和PM ESTA通过CCL 1/CCR 8，作为腹腔免疫反应的PMCs和招聘的机制。在这里，我们发现了一种有效的防御机制，作为一个特定的功能，腹腔巨噬细胞时，炎症或手术应激达到体内深处。