Connor Thomas J, Kelly John P
Department of Pharmacology, National University of Ireland, Galway, Ireland.
Eur J Pharmacol. 2002 Nov 29;455(2-3):175-85. doi: 10.1016/s0014-2999(02)02588-8.
We examined the immunomodulatory potential of acute fenfluramine administration, by measuring production of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in response to an in vivo challenge with bacterial lipopolysaccharide in rats. Fenfluramine (2.5-10 mg/kg) suppressed tumor necrosis factor-alpha production, but only fenfluramine (5 and 10 mg/kg) suppressed interleukin-1beta production. Fenfluramine (10 mg/kg)-induced suppression of interleukin-1beta and tumor necrosis factor-alpha production persisted for 6 and 24 h, respectively. Using in vitro analyses, we demonstrated that the immunosuppressive effect of fenfluramine was not due to a direct effect on immune cells. As fenfluramine activates the hypothalamic pituitary adrenal axis, we examined the ability of the glucocorticoid receptor antagonist mifepristone to block fenfluramine-induced immunosuppression. However, mifepristone (10 mg/kg) failed to attenuate the suppressive effect of fenfluramine on interleukin-1beta and tumor necrosis factor-alpha production, indicating that glucocorticoids do not mediate fenfluramine-induced immunosuppression. We also assessed the effect of fenfluramine on production of the anti-inflammatory cytokine interleukin-10, as interleukin-10 can suppresses pro-inflammatory cytokine production. Fenfluramine (10 mg/kg) increased interleukin-10 production following an in vivo lipopolysaccharide challenge. However, the ability of fenfluramine to suppress tumor necrosis factor-alpha production cannot be accounted for by increased interleukin-10 production, as pretreatment with the beta-adrenoceptor antagonist nadolol completely blocked the increase in interleukin-10 without altering the suppression of tumor necrosis factor-alpha induced by fenfluramine. Taken together, these data demonstrate that fenfluramine promotes an immunosuppressive cytokine phenotype in vivo. The suppression of pro-inflammatory cytokines is not due to a direct effect the drug on immune cells, and also occurs independently of glucocorticoid receptor activation. In addition, whilst fenfluramine increases production of the anti-inflammatory cytokine interleukin-10, this cannot account for the suppression of the pro-inflammatory cytokine tumor necrosis factor-alpha induced by fenfluramine.
我们通过测量大鼠体内注射细菌脂多糖后促炎细胞因子白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α的产生，来研究急性给予芬氟拉明的免疫调节潜力。芬氟拉明（2.5 - 10毫克/千克）可抑制肿瘤坏死因子-α的产生，但只有芬氟拉明（5和10毫克/千克）可抑制白细胞介素-1β的产生。芬氟拉明（10毫克/千克）诱导的白细胞介素-1β和肿瘤坏死因子-α产生的抑制分别持续6小时和24小时。通过体外分析，我们证明芬氟拉明的免疫抑制作用并非由于对免疫细胞的直接作用。由于芬氟拉明激活下丘脑-垂体-肾上腺轴，我们研究了糖皮质激素受体拮抗剂米非司酮阻断芬氟拉明诱导的免疫抑制的能力。然而，米非司酮（10毫克/千克）未能减弱芬氟拉明对白细胞介素-1β和肿瘤坏死因子-α产生的抑制作用，表明糖皮质激素并不介导芬氟拉明诱导的免疫抑制。我们还评估了芬氟拉明对抗炎细胞因子白细胞介素-10产生的影响，因为白细胞介素-10可抑制促炎细胞因子的产生。芬氟拉明（10毫克/千克）在体内脂多糖刺激后增加了白细胞介素-10的产生。然而，芬氟拉明抑制肿瘤坏死因子-α产生的能力不能通过白细胞介素-10产生的增加来解释，因为用β-肾上腺素能受体拮抗剂纳多洛尔预处理完全阻断了白细胞介素-10的增加，而未改变芬氟拉明诱导的肿瘤坏死因子-α的抑制作用。综上所述，这些数据表明芬氟拉明在体内促进了一种免疫抑制细胞因子表型。促炎细胞因子的抑制并非由于药物对免疫细胞的直接作用，并且也独立于糖皮质激素受体激活而发生。此外，虽然芬氟拉明增加了抗炎细胞因子白细胞介素-10的产生，但这不能解释芬氟拉明诱导的促炎细胞因子肿瘤坏死因子-α的抑制作用。
