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Adrenomedullin, a new peptidergic factor regulating inflammation and proliferation

肾上腺髓质素，一种调节炎症和增殖的新肽能因子

基本信息

批准号：
10218211
负责人：
MINAMINO Naoto
金额：
$ 42.05万
依托单位：
National Cardiovascular Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2002
项目状态：
已结题

项目摘要

To elucidate the regulatory effects of adrenomedullin (AM) in the inflammation and proliferation, we investigated its effects on primary cultured rat skin fibroblasts and keratinocytes. AM suppressed proliferation of the fibroblasts in the presence of 1% fetal bovine serum and regulated the production of cytokines and growth factors in them. AM production in the fibroblasts was dynamically regulated by cytokines, hormones and inflammation-related reagents, while that in the keratinocytes remained unchanged by these substances. The receptors expressed on the fibroblasts were specific for AM, while those on the keratinocytes for calcitonin gene-related peptide (CGRP). Taken together, AM in the skin is deduced to regulate the vasodilation, proliferation, production of cytokines and growth factors mainly through the fibroblasts.By monitoring the cAMP production in LLC-PK_1 of a pig renal epithelial cell line, we screened new peptides in the acid extracts of pig brain. We found several candidates of unidentified bioactive peptides, and finally purified one peptide. By structural analysis, this peptide was verified to be a 38-residue peptide with a C-terminal amide and a disulfide linkage, and showed higher sequence homology to CGRP. This peptide reduced the plasma calcium concentration instead of the blood pressure, and stimulated the calcitonin (CT) receptor at the potency much higher than that of CT. Thus, we designated it as CT receptor-stimulating peptide (CRSP). The discovery of CRSP led us to recognize the complexity of the CT/CGRP superfamily that consists of CT, CGRP, AM, amylin and CRSP.

为了阐明肾上腺髓质素(AM)在炎症和增殖中的调节作用，我们研究了它对原代培养的大鼠皮肤成纤维细胞和角质形成细胞的影响。含1%胎牛血清的AM可抑制成纤维细胞的增殖，并调节细胞因子和生长因子的产生。成纤维细胞中AM的产生受到细胞因子、激素和炎症相关物质的动态调节，而角质形成细胞中AM的产生不受这些物质的影响。成纤维细胞上表达的受体为AM特异性受体，角质形成细胞上表达的受体为降钙素基因相关肽(CGRP)受体。综上所述，皮肤中的AM主要通过成纤维细胞调节血管扩张、增殖、细胞因子和生长因子的产生。通过监测猪肾上皮细胞系LLC-PK_1中cAMP的产生，我们从猪脑的酸性提取物中筛选出新的多肽。我们发现了几个未知的生物活性多肽，并最终纯化了一个多肽。通过结构分析，证实该多肽是一个含有38个残基的多肽，具有C-端酰胺和二硫键，并与CGRP有较高的序列同源性。该多肽可降低血浆钙浓度，而不是降低血压，并以远高于降钙素(CT)受体的强度刺激降钙素受体。因此，我们将其命名为CT受体刺激肽(CRSP)。CRSP的发现使我们认识到CT/CGRP超家族的复杂性，该超家族由CT、CGRP、AM、胰淀素和CRSP组成。