Bissonnette E Y, Enciso J A, Befus A D
Department of Medicine, University of Alberta, Edmonton, Canada.
Clin Exp Immunol. 1995 Oct;102(1):78-84. doi: 10.1111/j.1365-2249.1995.tb06639.x.
TNF-alpha is a cytokine thought to be involved in the pathogenesis of asthma and in several other inflammatory conditions. Given recent evidence that mast cells (MC) are an important source of TNF-alpha, we investigated the effects of two anti-inflammatory drugs, nedocromil sodium (NED) and sodium cromoglycate (SCG), on rat MC-derived TNF-alpha. We established that at least 2 h pretreatment with NED or SCG followed by washing was required to inhibit TNF-alpha-dependent cytotoxicity by rat peritoneal MC (PMC). A maximum inhibition of TNF-alpha occurred after 6 h treatment. The inhibitory effect of NED and SCG (10(-5)-10(-3)M) was concentration-dependent (20-37% for NED and 16-37% for SCG). The time-course analysis and the use of cycloheximide, an inhibitor of protein synthesis, provided strong evidence that new protein synthesis by the MC is required for this inhibitory effect. Furthermore, 24 h treatment with 1 mM NED inhibited the levels of mRNA for TNF-alpha by 59-83%. In addition to the effect on TNF-alpha-dependent cytotoxicity by MC, 20 min pretreatment with 10(-4) M NED and SCG inhibited antigen-stimulated TNF-alpha release (6h) by 42% and 48%, respectively. Interestingly, the functionally distinct intestinal mucosal MC (IMMC) is unresponsive to these drugs with regard to histamine secretion. However, as with PMC, 2h pretreatment with NED or SCG inhibited TNF-alpha-dependent cytotoxicity by IMMC. These effects may be important in the action of these drugs in vivo in the late phase reaction in asthma or other inflammatory conditions.
肿瘤坏死因子-α（TNF-α）是一种细胞因子，被认为参与了哮喘及其他几种炎症性疾病的发病机制。鉴于最近有证据表明肥大细胞（MC）是TNF-α的重要来源，我们研究了两种抗炎药物奈多罗米钠（NED）和色甘酸钠（SCG）对大鼠MC来源的TNF-α的影响。我们确定，用NED或SCG预处理至少2小时，然后冲洗，才能抑制大鼠腹膜肥大细胞（PMC）的TNF-α依赖性细胞毒性。治疗6小时后，TNF-α的抑制作用达到最大。NED和SCG（10⁻⁵ - 10⁻³M）的抑制作用呈浓度依赖性（NED为20 - 37%，SCG为16 - 37%）。时间进程分析以及使用蛋白质合成抑制剂环己酰亚胺提供了有力证据，表明MC的新蛋白质合成是这种抑制作用所必需的。此外，用1 mM NED处理24小时可使TNF-α的mRNA水平降低59 - 83%。除了对MC的TNF-α依赖性细胞毒性有影响外，用10⁻⁴M NED和SCG预处理20分钟分别抑制抗原刺激的TNF-α释放（6小时）42%和48%。有趣的是，功能不同的肠道黏膜肥大细胞（IMMC）在组胺分泌方面对这些药物无反应。然而，与PMC一样，用NED或SCG预处理2小时可抑制IMMC的TNF-α依赖性细胞毒性。这些作用可能在这些药物在哮喘或其他炎症性疾病的体内晚期反应中的作用中很重要。
