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

我们重点研究了出现在唾液腺、口腔黏膜和其他组织中的肥大细胞，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腔中的肥大细胞表达了高分子量的激肽原和T-I激肽原，这些蛋白产物储存在这些细胞的分泌颗粒中（2000-2001）。另一方面，除肥大细胞外的唾液腺细胞未显示激肽原表达，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外的各种细胞因子。因此，我们研究了这些细胞因子的表达是如何受到口腔或全身炎症信号的调节的。我们也试图找出唾液腺在口腔防御系统中的作用。以C3H/HeJ和C3H…More /HeN小鼠（toll样受体缺陷突变株及其野生型株）为实验对象，研究了全身注射LPS对炎症因子的诱导作用。在体内实验中，注射LPS强烈诱导n-1β的表达，弱诱导TNF-α和IL-6的表达（2002）。我们随后发现IL-lei定位于颗粒状卷管细胞的分泌颗粒。我们还发现唾液腺IL-1β的大小为17 kDa，尽管在颌下腺中合成了与35 kDa IL-1β前体相对应的mRNA。因此可以想象，35 kDa的IL-1β前体在唾液腺中被水解成17 kDa的分泌形式。由于缓激因子mK1、mK9、mK13和mK22定位于颌下腺分泌颗粒中，我们用这些缓激因子培养35 kDa IL-1β。结果表明，mK13是一种产生17 kDa IL-1β的酶。我们目前正在研究mk13在35kda IL-1β中的切割位点，口腔是人体有害外来抗原或细菌的主要屏障，因此需要严格的防御系统。本研究提示存在“口腔唾液腺轴”作为防御系统，发生在口腔内的炎症可通过与唾液腺的相互作用而愈合

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