Tumor necrosis factor α decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone:: Potential regulation of the glucocorticoid receptor
Tumor necrosis factor α decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone:: Potential regulation of the glucocorticoid receptor
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DOI：
10.1210/jc.84.8.2834
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发表时间：
1999-08-01
影响因子：
5.8
通讯作者：
Geenen, V
中科院分区：
文献类型：
--
作者：
Franchimont, D;Martens, H;Geenen, V
在自身免疫性/炎症性疾病患者中观察到对糖皮质激素治疗的抵抗，可能与炎症过程本身有关。本研究的目的是检查肿瘤坏死因子α（TNF α，一种促炎细胞因子）和白细胞介素（IL）-10（一种抗炎细胞因子）差异调节人单核细胞/巨噬细胞对糖皮质激素敏感性的能力。为了实现这一点，我们首先分析了LPS刺激的全血细胞培养物中地塞米松对TNF α和IL-10抑制的模式。第二，我们研究了这些细胞对地塞米松的敏感性的调制，通过与TNF α或IL-10预孵育和测量LPS刺激的IL-6分泌。此外，我们评估了地塞米松对佛波醇肉豆蔻酸酯乙酸酯刺激的人单核细胞系U937分泌IL-1受体拮抗剂的影响。最后，我们研究了TNF α和IL-10预处理的U937细胞中皮质敏感性的调节是否与糖皮质激素受体浓度和亲和力的变化有关。地塞米松对LPS诱导的TNF α和IL-10分泌有不同的影响;虽然它以剂量依赖性方式抑制TNF α，但它对IL-10分泌的影响是双相的，在较低剂量时产生刺激，在较高剂量时产生抑制。LPS浓度影响地塞米松对IL-10分泌的影响（P < 0.001）。用TNF α预处理降低了地塞米松抑制全血细胞培养物中IL-6分泌的能力（两者P < 0.01），并提高了U937细胞分泌IL-1受体拮抗剂的能力（两者P <0.05），而用IL-10预处理则提高了地塞米松的这种能力。TNF α降低（P < 0.001），而IL-10增加（P < 0.001），这些细胞中地塞米松结合位点的浓度，对其结合亲和力没有明显影响。我们的结论是，糖皮质激素差异调节TNF α和IL-10分泌的人单核细胞在LPS剂量依赖性的方式，这些细胞对糖皮质激素的敏感性被改变的TNF α或IL-10的预处理; TNF α阻断其作用，而IL-10与糖皮质激素协同作用。这伴随着相反的糖皮质激素受体的变化，分别反对和有利于糖皮质激素的作用。这项研究表明，前/后细胞因子分泌的模式可能会改变患者对糖皮质激素治疗的反应。
Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNF alpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNF alpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNF alpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbol-myristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNF alpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNF alpha and IL-10 secretion; whereas it suppressed TNF alpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNF alpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNF alpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNF alpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNF alpha or IL-10 pretreatment; TNF alpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy.