Pyrogens are classified in two groups, endotoxin pyrogens and non-endotoxin pyrogens (NEPs). The presence of either in parenteral pharmaceuticals or medical devices can cause severe harm to subjects, and when occurring in combination, synergistic potentiation effects can occur. As the standard in vitro pyrogen test, the Limulus Amebocyte Lysate (LAL) assay can detect LPS only, an endotoxin, but not NEPs. We tested whether the Monocyte Activation Test (MAT) that measures IL-6 induction, is suited for detecting synergistic pyrogen effects. Here we show that MAT reliably detects the NEPs heat-killed Staphylococcus aureus, R848 and lipoteichoic acid, in addition to LPS. When combinations of these pyrogens were tested, a potentiation of IL-6 production was seen beyond an additive effect, apparently reflecting on in-vivo synergisms. The current study therefore demonstrates that MAT not only is a reliable and reproducible assay for the sensitive detection of both endotoxin and non-endotoxin pyrogens, but also for identifying synergistic effects when parenteral drugs are contaminated with multiple pyrogens.

热原分为两类，内毒素热原和非内毒素热原 (NEP)。肠胃外药物或医疗器械中的任何一种都可能对受试者造成严重伤害，并且当组合发生时，可能会产生协同增效作用。作为标准的体外热原测试，鲎变形细胞裂解物 (LAL) 测定只能检测 LPS（一种内毒素），但不能检测 NEP。我们测试了测量 IL-6 诱导的单核细胞活化测试 (MAT) 是否适合检测协同热原效应。在这里，我们表明 MAT 能够可靠地检测 NEPs 热灭的金黄色葡萄球菌, R848 和脂磷壁酸，除了 LPS。当测试这些热原的组合时，IL-6 产生的增强作用超出了累加效应，显然反映了体内协同作用。因此，目前的研究表明，MAT 不仅是一种可靠且可重复的检测方法，可以灵敏地检测内毒素和非内毒素热原，而且当肠外药物被多种热原污染时，它还可以识别协同效应。