Inflammatory cytokines stimulate adrenomedullin expression through nitric oxide-dependent and -independent pathways
Inflammatory cytokines stimulate adrenomedullin expression through nitric oxide-dependent and -independent pathways
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DOI：
10.1161/hy1201.097201
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发表时间：
2002-01-01
期刊：
影响因子：
8.3
通讯作者：
Sandner, P
中科院分区：
文献类型：
--
作者：
Hofbauer, KH;Schoof, E;Sandner, P
大量证据表明，肾上腺髓质素（ADM）在体内的产生在炎症状态下被激活。我们的目的是表征细胞内信号通路沿着炎症导致ADM表达的刺激。为此，我们研究了炎症细胞因子，肿瘤坏死因子-α（100 μ g/L），白细胞介素-1 β（20 μ g/L）和干扰素-γ（0.5 U/L）对大鼠主动脉血管平滑肌细胞（AVSMCs）中ADM基因表达的影响。我们发现，炎性细胞因子诱导AVSMCs中ADM mRNA的时间依赖性12倍上调，这是由诱导型NO合酶mRNA表达的大幅增加引起的。细胞因子对ADM基因表达的刺激作用可被Nomega-硝基-L-精氨酸甲酯（1 mmol/L）诱导的NO剥夺所减弱，并被NO供体S-亚硝基-N-乙酰青霉胺（100 mumol/L）部分模拟。cGMP类似物8-bromo-cGMP（100 mumol/L）对ADM基因表达无影响，1H-oxodiazolo-quinoxalin-1（ODQ，200 mumol/L）抑制cGMP的产生也不能消除S-亚硝基-N-乙酰青霉胺（100 mumol/L）诱导的ADM基因表达的增加。在系膜细胞、内皮细胞和肝细胞中也观察到炎性细胞因子和NO供体对ADM基因表达的显著诱导。这些结果表明，NO是一个直接激活剂的ADM基因表达在各种类型的细胞和炎症细胞因子刺激ADM表达通过NO依赖性和非依赖性机制。NO的刺激作用似乎与经典的鸟苷酸环化酶-cGMP途径无关。
A body of evidence indicates that the production of adrenomedullin (ADM) in vivo is activated in states of inflammation. Our aim was to characterize the intracellular signaling pathways along which inflammation leads to a stimulation of ADM expression. For this purpose, we characterized the effects of inflammatory cytokines, tumor necrosis factor-alpha (100 mug/L), interleukin-1beta (20 mug/L), and interferon-gamma (0.5 U/L) on ADM gene expression in rat aortic vascular smooth muscle cells (AVSMCs). We found that inflammatory cytokines induced a time-dependent 12-fold upregulation of ADM mRNA in AVSMCs that was paralleled by a substantial increase in inducible NO synthase mRNA expression. The stimulatory effect of cytokines on ADM gene expression was attenuated by NO deprivation induced by Nomega-nitro-L-arginine methyl ester (1 mmol/L) and was in part mimicked by the NO donor S-nitroso-N-acetylpenicillamine (100 mumol/L). The cGMP analog 8-bromo-cGMP (100 mumol/L) had no effect on ADM gene expression, and inhibition of cGMP production by 1H-oxodiazolo-quinoxalin-1 (ODQ, 200 mumol/L) was not able to abrogate the increase of ADM mRNA induced by NO donation using S-nitroso-N-acetylpenicillamine (100 mumol/L). The significant induction of ADM gene expression by inflammatory cytokines and NO donation was also observed in mesangial cells, endothelial cells, and hepatocytes. These findings suggest that NO is a direct activator of ADM gene expression in a variety of cell types and that inflammatory cytokines stimulate ADM expression via both NO-dependent and -independent mechanisms. The stimulatory effect of NO appears to not be related to the classic guanylate cyclase-cGMP pathway.