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Inflammation by mast cell kininogen and its suppression -Development of a new drug

肥大细胞激肽原引起的炎症及其抑制-新药的开发

基本信息

批准号：
13557154
负责人：
HOSOI Kazuo
金额：
$ 7.62万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557154/
关键词：
Kininogen Acute phase protein Inflammation cytokine LPS exocrine gland Salivary gland

项目摘要

We have focussed on the mast cells appearing in salivary gland, oral mucosa, and other tissues, and examined the bioactive substances present in these cells. We found that the mast cells present in these tissues and peritoneal cavity expressed high molecular weight-kininogen and T-I kininogen and these protein products were stored in the secretory granules in these cells (2000-2001). On the other hand, the salivary gland cells other than mast cells did not show the kininogen expression, although there are reports indicating that these inflammation proteins are expressed in the salivary gland parenchymal cellsOn the other hand, the salivary gland produces the various cytokins other than these inflammation proteins. We therefore examined how the expression of these cytokines are regulated by the inflammation signals prompted in the oral cavity or in the whole body. We also tried to find out the function of the salivary gland in the defense system in the oral cavity. Using C3H/HeJ and C3H … More /HeN mice (mutant strain defective of Toll-like receptor and its wild type strain), we examined how inflammation cytokines were induced by systemic injection of LPS. In vivo experiments, injection of LPS induced the expression of n-1β strongly and TNF-α and IL-6 weakly (2002)We next showed that IL-lei was localized in the secretory granules of the granular convoluted tubular cells. We also found that the size of salivary gland IL-1β is 17 kDa although the mRNA corresponding to 35 kDa IL-1β precursor was synthesized in the submandibular gland. It is therefore conceivable that 35 kDa IL-1β precursor was hydrolyzed to the 17 kDa secretory form in the salivary gland. Since kallikrein mK1, mK9, mK13, and mK22 are localized in the secretory granules of the submandibular gland, we incubated 35 kDa IL-1β with these kallikreins. The result showed that mK13 is an enzyme which gave 17 kDa IL-1β. We are now investigating the cleavage site in 35 kDa IL-1β by mK13Strict defense system would be required for oral cavity since the oral cavity is a major barrier of harmful foreign antigens or bacteria in the body. The present study implies the existence of "Oral cavity Salivary gland axis" as a defense system, by which inflammation occurred in the oral cavity may be healed by interaction with the salivary gland Less

我们关注唾液腺、口腔粘膜和其他组织中出现的肥大细胞，并检查了这些细胞中存在的生物活性物质。我们发现这些组织和腹膜腔中存在的肥大细胞表达高分子量激肽原和T-I激肽原，并且这些蛋白质产物储存在这些细胞的分泌颗粒中(2000-2001)。另一方面，肥大细胞以外的唾液腺细胞不显示激肽原表达，尽管有报道表明这些炎症蛋白在唾液腺实质细胞中表达。另一方面，唾液腺产生除这些炎症蛋白之外的各种细胞因子。因此，我们研究了这些细胞因子的表达如何受到口腔或全身提示的炎症信号的调节。我们还试图找出唾液腺在口腔防御系统中的功能。使用 C3H/HeJ 和 C3H … 更多 /HeN 小鼠（Toll 样受体缺陷的突变株及其野生型株），我们研究了全身注射 LPS 如何诱导炎症细胞因子。体内实验中，注射 LPS 强烈诱导 n-1β 的表达，并弱诱导 TNF-α 和 IL-6 的表达（2002）我们接下来表明 IL-lei 位于颗粒曲管细胞的分泌颗粒中。我们还发现唾液腺IL-1β的大小为17 kDa，尽管对应于35 kDa IL-1β前体的mRNA是在下颌下腺中合成的。因此可以想象，35 kDa IL-1β 前体在唾液腺中被水解为 17 kDa 的分泌形式。由于激肽释放酶 mK1、mK9、mK13 和 mK22 位于颌下腺的分泌颗粒中，因此我们将 35 kDa IL-1β 与这些激肽释放酶一起孵育。结果表明mK13是一种产生17 kDa IL-1β的酶。我们现在正在研究 mK13 对 35 kDa IL-1β 的切割位点。口腔需要严格的防御系统，因为口腔是体内有害外来抗原或细菌的主要屏障。本研究暗示存在“口腔唾液腺轴”作为防御系统，口腔发生的炎症可以通过与唾液腺的相互作用来治愈。