Production and function of adrenomedullin in the extro-cardiovascular system

肾上腺髓质素（AM）是在嗜铬细胞组组织中发现的一种新型血管松弛肽。AM可在血管平滑肌细胞（VSMC）和内皮细胞（EC）中产生。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。在EC中AM的产生与VSMC的调节基本相似，溶血磷脂酰胆碱和氧化LDL增加了EC中AM的产生。由于AM抑制VSMC的增殖，AM有望抑制动脉粥样硬化。作为血管外细胞，我们检测了3个成纤维细胞和3个单核/巨噬细胞系。所有这些细胞都产生AM。特别是人成纤维细胞分泌AM量高。成纤维细胞对AM产生的调节主要类似于VSMC。由于Swiss 3T3成纤维细胞表达AM特异性受体，我们检测了AM对该细胞系的影响。AM能刺激Swiss 3T3细胞的增殖，其效力相当于10%胎牛血清的75%以上。AM使IL-6的产生增加5.5倍，与tnf - α、il -1 β或LPS共给药可协同增强其作用。事实上，AM与tnf - α的结合使IL-6的产生增加了近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在单核细胞/巨噬细胞中产生，但其分泌率低于VSMC和成纤维细胞。单核细胞/巨噬细胞向巨噬细胞分化，AM的产生随之增加。tnf - α， il -1 β和LPS刺激AM的产生，当这些物质与佛博尔酯和视黄酸一起使用时，通常会引起协同效应。ifn - γ增加，但糖皮质激素抑制AM的产生，这与EC和VSMC的调控形成鲜明对比。AM抑制lps刺激的tnf - α和11l -6产生20-50%。这些结果表明AM抑制单核细胞/巨噬细胞的炎症反应。通过这个项目，发现AM在多种细胞中产生，以响应炎症刺激。本研究结果提示AM作为抑制因子参与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