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CELLULAR INVESTIGATION AND ANALYSIS OF INDUCTION MECHANISMS OF IN VITRO LANGHANS TYPE-MULTINUCLEATED GIANT CELL FORMATION

体外郎罕斯型多核巨细胞形成诱导机制的细胞研究与分析

基本信息

批准号：
11670855
负责人：
OKAMOTO Hiroyuki
金额：
$ 1.79万
依托单位：
KANSAI MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670855/
关键词：
Granuloma Sarcoidosis Multinucleated Giant Cells MDP Langhans-type Foreign body-type CD14 CD16 Tranilast 単球

项目摘要

The supernatant of concanavalin A-stimulated human peripheral blood mononuclear cells (conditioned medium) generated multinucleated giant cells (MGC) ; Langhans type-(LGC) and foreign body type-MGC (FGC). MDP (N-acetylmuramyl-L-alanyl-D-isoglutamine), a structural analogue of part of the bacterial peptidoglycan, augmented the frequency of LGC.Adhesion molecules and cytokines such as IFN-γ, GM-CSF and IL-3 were found to play an important role in MGC formation but not in LGC induction. Extracellular matrix was also important for MGC formation, particularly cellular fibronectin for LGC induction. MGC were produced by conditioned medium from CD 14^<++> CD 16 monocytes but not from CD 14^+CD16^+ monocytes or immature dendritic cells induced by GM-CSF and IL-4, and slightly from macrophages induced by M-CSF.Addition of MDP did not generate MGC from CD14^+CD16^+ monocytes or dendritic cells but slightly enhanced LGC formation from macrophages. Fusion index of LGC from CD 14^<++> CD16^+ monocytes were enhanced by MDP as same as that in whole monocytes. Next, we examined MGC formation from monocytes of patients with sarcoidosis. MGC were more highly produced from monocytes of sarcoidosis patients than healthy control subjects. The susceptibility of monocytes cultured in conditioned medium for 24 hrs to Bz-ATP-mediated cytolysis was significantly higher in sarcoidosis patients than normal subjects, suggesting that the ability of monocytes to produce MGC through purinergic receptors was enhanced in sarcoidosis patients. Finally, we examined the in vitro effect of tranilast on the formation of MGC.Tranilast inhibited the formation of both types of MGC dose-dependently. Immuno-histochemical stainings showed that tranilast-treated monocytes had less expression of ICAM-1. These findings suggest that tranilast has an efficacy for cutaneous lesions in some cases of granulomatous disorders partly through a direct effect on monocyte/macrophage-lineage cells.

伴刀豆球蛋白A刺激人外周血单个核细胞的上清液（条件培养基）产生多核巨细胞（MGC）、Langhans型（LGC）和异物型（FGC）。MDP（N-acetylmuramyl-L-alanyl-D-isoglutamine，N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰胺）是细菌肽聚糖的一种结构类似物，可增加LGC的发生率，而粘附分子和细胞因子如IFN-γ、GM-CSF和IL-3在MGC的形成中起重要作用，但在LGC的诱导中不起作用。细胞外基质对MGC的形成也很重要，特别是细胞纤连蛋白对LGC的诱导。条件培养液中CD 14^++ CD 16单核细胞不能产生MGC，而CD 14^+ CD 16 ^+单核细胞或未成熟树突状细胞不能产生MGC，M-CSF诱导的巨噬细胞也不能产生MGC，MDP不能诱导CD 14 ^+ CD 16 ^+单核细胞或树突状细胞产生MGC，但能促进巨噬细胞产生LGC。MDP可增强CD 14^<++> CD 16 ^+单核细胞的LGC融合指数，与完整单核细胞的LGC融合指数相同。接下来，我们检测了结节病患者单核细胞的MGC形成。结节病患者的单核细胞产生MGC的水平高于健康对照组。在条件培养基中培养24小时的单核细胞对Bz-ATP介导的细胞溶解的敏感性在结节病患者中明显高于正常受试者，这表明结节病患者单核细胞通过嘌呤能受体产生MGC的能力增强。最后，我们研究了曲尼司特在体外对MGC形成的影响，曲尼司特剂量依赖性地抑制两种类型MGC的形成。免疫组织化学染色显示曲尼司特处理的单核细胞ICAM-1表达减少。这些发现表明曲尼司特对某些肉芽肿性疾病的皮肤病变有效，部分是通过对单核细胞/巨噬细胞系细胞的直接作用。