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Molecular biological properties of lipidA derived from chronic inflammatory pathogens

慢性炎症病原体脂质A的分子生物学特性

基本信息

批准号：
09671848
负责人：
OGAWA Tomohiko
金额：
$ 1.92万
依托单位：
Asahi University (1998)Osaka University (1997)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671848/
关键词：
lipid A LPS Helicobacter pylori Porphyromonas gingivalis compound 506 Endotoxic property Immunobiological activity Cytokine

项目摘要

Helicobacter pylori lipid A exhibited no or very low endotoxic activities i.e., lethal toxicity in galactosamine-loaded mice, pyrogenicity for rabbits and the activity of the Limulus test when compared with Escherichia coli-type synthetic lipid A (compound 506). The endotoxic properties of H.pylon lipid A were also a little weaker than those of the low endotoxic lipid A of P.gingivalis. The mitogenic activity of H.pylori lipid A in murine splenic mononuclear cells was also less than those of P.gingivalis lipid A and compound 506. On the other hand, H.pylori lipid A induced comparable production of interleukin-6 (IIL-6) by human peripheral blood mononuclear cells (PBMC) as compared with P.gingivalis lipid A and compound 506. H.pylori lipid A also increased definitely human natural killer cell activity, and strongly agglutinated rabbit erythrocytes. However, the lipid As of H.pylori and P.gingivalis showed lower activities in inducing tumor necrosis factor alpha (TNF-alpha) production by human PBMC and IL-8 production by human gingival fibroblasts than that of compound 506. The structural feature of H.pylori lipid A may be associated with low endotoxic properties and potent immunobiological activities. Futher, a systemic infection by Gram-negative bacteria results in septic shock which is mainly caused by macrophages stimulated with endotoxic lipopolysaccharides (LPS). The administration of non-toxic lipid A of P.gingivalis results in lower induction of IL-1beta production and its mRNA expression, whereas the lipid A exhibited higher calmodulin kinase activation in comparison with that of endotoxic synthetic lipid A of E.coli in alveolar macrophages of galactosamine-loaded mice. A calmodulin kinase activator and anti-IL-beta monoclonal antibody also protected mice against endotoxic lipid A-induced lethal toxicity.

与大肠杆菌型合成脂质A（化合物506）相比，幽门螺杆菌脂质A没有或表现出极低的内毒活性，即对半乳糖胺负荷小鼠具有致死毒性，对家兔具有热原性和鲎试验活性。与低内毒的牙龈假单胞菌脂质A相比，H.pylon脂质A的内毒性能也稍弱。幽门螺杆菌脂质A在小鼠脾单核细胞中的有丝分裂活性也低于龈门螺杆菌脂质A和化合物506。另一方面，幽门螺旋杆菌脂质A诱导人外周血单个核细胞（PBMC）产生白细胞介素6 （il -6）的能力与牙龈螺旋杆菌脂质A和化合物506相当。幽门螺杆菌脂质A也能明显提高人自然杀伤细胞活性，并能强烈凝集家兔红细胞。然而，幽门螺杆菌和牙龈假单胞杆菌的脂质As诱导人PBMC产生肿瘤坏死因子α (tnf - α)和人牙龈成纤维细胞产生IL-8的活性低于化合物506。幽门螺杆菌脂质A的结构特征可能与低内毒特性和强大的免疫生物学活性有关。此外，革兰氏阴性菌的全身感染导致脓毒性休克，这主要是由内毒素脂多糖（LPS）刺激巨噬细胞引起的。在半乳糖胺负荷小鼠的肺泡巨噬细胞中，给药无毒的牙龈假单胞菌脂质A诱导il -1 β的产生及其mRNA表达较低，而与内毒的大肠杆菌合成脂质A相比，脂质A表现出更高的钙调蛋白激酶激活。钙调蛋白激酶激活剂和抗il - β单克隆抗体也能保护小鼠免受内毒素脂质A诱导的致死毒性。