Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Sci Rep. 2017 Jan 5;7:40050. doi: 10.1038/srep40050.
Monophosphoryl lipid A (MPLA), a less toxic derivative of lipopolysaccharide (LPS), is employed as a vaccine adjuvant and is under investigation as a non-specific immunomodulator. However, the differential response of human leukocytes to MPLA and LPS has not been well characterized. The goal of this study was to compare the differential transcriptomic response of human blood to LPS and MPLA. Venous blood from human volunteers was stimulated with LPS, MPLA or vehicle. Gene expression was determined using microarray analysis. Among 21,103 probes profiled, 136 and 130 genes were differentially regulated by LPS or MPLA, respectively. Seventy four genes were up-regulated and 9 were down-regulated by both ligands. The remaining genes were differentially induced by either agent. Ingenuity Pathway Analysis predicted that LPS and MPLA share similar upstream regulators and have comparable effects on canonical pathways and cellular functions. However, some pro-inflammatory cytokine and inflammasome-associated transcripts were more strongly induced by LPS. In contrast, only the macrophage-regulating chemokine CCL7 was preferentially up-regulated by MPLA. In conclusion, LPS and MPLA induce similar transcriptional profiles. However, LPS more potently induces pro-inflammatory cytokine and inflammasome-linked transcripts. Thus, MPLA is a less potent activator of the pro-inflammatory response but retains effective immunomodulatory activity.
单磷酰脂质 A（MPLA）是脂多糖（LPS）的一种毒性较低的衍生物，被用作疫苗佐剂，并被作为一种非特异性免疫调节剂进行研究。然而，人类白细胞对 MPLA 和 LPS 的反应差异尚未得到很好的描述。本研究旨在比较人血对 LPS 和 MPLA 的差异转录组反应。志愿者静脉血用 LPS、MPLA 或载体刺激。使用微阵列分析测定基因表达。在 21103 个探针中，LPS 或 MPLA 分别调节了 136 和 130 个基因。两种配体均上调 74 个基因，下调 9 个基因。其余基因由任一试剂差异诱导。Ingenuity 通路分析预测 LPS 和 MPLA 具有相似的上游调节剂，对经典通路和细胞功能具有相似的影响。然而，一些促炎细胞因子和炎症小体相关转录物被 LPS 更强地诱导。相比之下，只有巨噬细胞调节趋化因子 CCL7 被 MPLA 优先上调。总之，LPS 和 MPLA 诱导相似的转录谱。然而，LPS 更强烈地诱导促炎细胞因子和炎症小体相关转录物。因此，MPLA 是一种较弱的促炎反应激活剂，但保留有效的免疫调节活性。
