Ruetten H, Thiemermann C
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
J Physiol Pharmacol. 1997 Dec;48(4):675-88.
Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
内皮素 -1（ET-1）可增强大鼠内皮细胞和骨髓来源的基质细胞中白细胞介素 -6（IL-6）的生物合成。本研究调查了：（i）ET-1是否能刺激培养的巨噬细胞或麻醉大鼠体内肿瘤坏死因子α（TNFα）或干扰素 -γ（IFNγ）的形成。用ET-1（0.001 - 1微摩尔）孵育J774.2巨噬细胞，导致培养基中TNFα浓度呈浓度和时间依赖性增加，但IFNγ浓度未增加。用以下物质预处理细胞可消除ET-1刺激J774.2巨噬细胞引起的TNFα增加：（i）蛋白质合成抑制剂环己酰亚胺；（ii）选择性ETA受体拮抗剂BQ-123或BQ-485（但不是选择性ETB受体拮抗剂BQ-788）；（iii）酪氨酸激酶抑制剂染料木黄酮或 tyrphostin AG126；（iv）糖皮质激素地塞米松。地塞米松对ET-1激活的细胞形成TNFα的抑制作用并非由于脂皮质素 -1（LC1）的形成，因为针对LC1的单克隆抗体并未使其减少。向麻醉大鼠静脉内注射ET-1（1纳摩尔·千克⁻¹）可导致血浆TNFα水平迅速且持续升高（最高：45分钟；恢复至基线：180分钟内）。这是首次证明ET-1可在体外和体内释放促炎细胞因子。ET-1引起的TNFα生成依次涉及：（i）ETA受体的激活；（ii）酪氨酸激酶的激活，导致细胞内蛋白质磷酸化；（iii）迄今未知的转录因子的激活，最终导致（iv）TNFα基因的转录和翻译。ET-1激活的细胞生成TNFα表明ET-1在与局部（如动脉粥样硬化、心力衰竭）或全身炎症（循环性休克）相关的疾病中具有促炎作用，这些疾病与血浆ET-1水平升高有关。
