Okemoto Kazuo, Kawasaki Kiyoshi, Hanada Kentaro, Miura Masami, Nishijima Masahiro
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan.
J Immunol. 2006 Jan 15;176(2):1203-8. doi: 10.4049/jimmunol.176.2.1203.
Lipid A, the membrane anchor portion of LPS, is responsible for the endotoxin activity of LPS and induces many inflammatory responses in macrophages. Monophosphoryl lipid A (MPL), a lipid A derivative lacking a phosphate residue, induces potent immune responses with low toxicity. To elucidate the mechanism underlying the low toxicity of MPL, we examined the effects of MPL on the secretion of proinflammatory cytokines by mouse peritoneal macrophages, a murine macrophage-like cell line (RAW 264.7), and a human macrophage-like cell line (THP-1). MPL enhanced the secretion of TNF-alpha, but not that of IL-1beta, whereas Escherichia coli-type lipid A (natural source-derived and chemically synthesized lipid A) enhanced the secretion of both cytokines. Although MPL enhanced the levels of IL-1beta mRNA and IL-1beta precursor protein to levels similar to those induced by lipid A, IL-1beta precursor processing in MPL-treated cells was much lower than that in E. coli-type lipid A-treated ones. Moreover, MPL, unlike E. coli-type lipid A, failed to induce activation of caspase-1, which catalyzes IL-1beta precursor processing. These results suggest that an immune response without activation of caspase-1 or secretion of IL-1beta results in the low toxicity of this adjuvant.
脂多糖（LPS）的膜锚定部分脂质A负责LPS的内毒素活性，并在巨噬细胞中诱导多种炎症反应。单磷酸脂质A（MPL）是一种缺少磷酸残基的脂质A衍生物，能诱导强烈的免疫反应且毒性较低。为阐明MPL低毒性的潜在机制，我们检测了MPL对小鼠腹腔巨噬细胞、鼠巨噬细胞样细胞系（RAW 264.7）和人巨噬细胞样细胞系（THP - 1）促炎细胞因子分泌的影响。MPL增强了肿瘤坏死因子-α（TNF-α）的分泌，但未增强白细胞介素-1β（IL-1β）的分泌，而大肠杆菌型脂质A（天然来源和化学合成的脂质A）增强了这两种细胞因子的分泌。尽管MPL将IL-1β mRNA和IL-1β前体蛋白水平提高到与脂质A诱导的水平相似，但MPL处理细胞中的IL-1β前体加工远低于大肠杆菌型脂质A处理的细胞。此外，与大肠杆菌型脂质A不同，MPL未能诱导半胱天冬酶-1的激活，而半胱天冬酶-1催化IL-1β前体的加工。这些结果表明，不激活半胱天冬酶-1或不分泌IL-1β的免疫反应导致了这种佐剂的低毒性。
