Production and function of adrenomedullin in the extro-cardiovascular system

肾上腺髓质素（AM）是一种在嗜铬细胞组织中发现的新型血管舒张肽。已证明AM在血管平滑肌细胞（VSMC）和内皮细胞（EC）中活跃产生。VSMC中AM的产生通过TNF-α、IL-1 β、脂多糖（LPS）和糖皮质激素的刺激而增强。EC中AM产生的调节与VSMC的调节基本相似，而溶血磷脂酰胆碱和氧化低密度脂蛋白可增加EC中AM的产生，AM抑制VSMC的增殖，因而有望抑制动脉粥样硬化。这些细胞都能分泌AM，尤其是人成纤维细胞分泌AM的量较高。由于Swiss 3 T3成纤维细胞表达AM特异性受体，我们研究了AM对该细胞系的影响。AM刺激Swiss 3 T3细胞增殖，其效力与 ...更多信息 是10%胎牛血清的75%。AM可使IL-6的产生增加5.5倍，与TNF-α、IL-1 β或LPS联合应用可使IL-6的产生增加近300倍。AM的增殖和刺激作用是由cAMP-蛋白激酶A系统介导的。AM由单核/巨噬细胞产生，但其分泌速率低于VSMC和成纤维细胞。单核/巨噬细胞中AM的产生根据它们向巨噬细胞的分化而增加。TNF-α、IL-1 β和LPS刺激AM产生，当与佛波酯和维甲酸一起给药时，这些物质通常引起协同效应。与EC和VSMC的调节作用形成鲜明对比的是，IFN-γ增加AM的产生，而糖皮质激素抑制AM的产生，AM抑制LPS刺激的TNF-α和IL-6的产生20- 50%。这些结果表明，AM抑制单核/巨噬细胞的炎症反应。本项目发现，AM在多种细胞中产生，以响应炎症刺激。提示AM作为一种抑制因子参与了炎症和动脉粥样硬化的调节。少

Adrenomedullin (AM) is a novel vasorelaxant peptide identified in pheochromocytome tissue. AM has been shown to be actively produced iii vascular smooth muscle cells (VSMC) and endothelial cells (EC). AM production in VSMC is augmented by the stimulation of TNF-alpha, IL-1beta, lipopolysaccharide (LPS) and glucocorticoid. Regulation of AM production in EC was principally similar to that of VSMC, and lysophosphatidylcholine and oxidized LDL increased AM production in EC.As AM inhibits proliferation of VSMC, AM is expected to suppress atherosclerosis.As extra-vascular cells, we examined 3 fibroblast and 3 monocyte/macrophage cell lines. All of these cells produced AM.Especially, human fibroblasts secreted AM at a high. Regulation of AM production in fibroblasts is principally similar to that of VSMC.Since Swiss 3T3 fibroblast expresses AM specific receptors, we examined the effects of AM on this cell line. AM stimulated proliferation of Swiss 3T3 cells, and its potency was comparable to … More 75% that of 10% fetal calf serum. AM increased IL-6 production 5.5 fold, and its effect was synergistically enhanced by co-administration with TNF-alpha, IL-1beta or LPS.In fact, administration of AM with TNF-alpha elevated IL-6 production nearly 300 fold. The proliferative and stimulatory effect of AM was mediated by the cAMP-protein kinase A systemAM is produced in monocyte/macrophage, but their secretion rates were lower than that of VSMC and fibroblasts. AM production in monocyte/macrophage was increased according to their differentiation into macrophages. TNF-alpha, IL-1beta and LPS stimulated AM production, and these substances often elicited synergistic effects when administered with phorbol ester and retinoic acid. IFN-gamma increased but glucocorticoid suppressed AM production, which showed the sharp contrast to the regulation in EC and VSMC.AM inhibited LPS-stimulated TNF-alpha and 1L-6 production 20-50%. These results indicate that AM inhibits inflammatory responses of the monocyte/macrophage.By this project, AM is found to be produced in variety of cells in response to the inflammatory stimuli. The present results suggest that AM participates in the regulation of inflammation and atherosclerosis as an inhibitory factor. Less