β-Adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IκB/NF-κB pathway
β-Adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IκB/NF-κB pathway
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DOI：
10.1152/ajplung.2000.279.4.l675
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发表时间：
2000-10-01
影响因子：
4.9
通讯作者：
Pugin, J
中科院分区：
文献类型：
--
作者：
Farmer, P;Pugin, J
除了充分研究的支气管扩张和强心剂作用外，β-肾上腺素能激动剂通过抑制人单核细胞产生细胞因子而具有抗炎特性。在脂多糖（LPS）刺激的人前单核细胞THP-1细胞模型中，我们发现β-受体激动剂主要通过β（2）-肾上腺素能受体产生cAMP和激活蛋白激酶A来抑制肿瘤坏死因子-α和白细胞介素-8的产生。这种作用被其他cAMP升高剂，如甘草素和cAMP类似物复制。LPS诱导的转录因子核因子-κ B的活化和核转位被β-激动剂处理抑制，该作用在晚期时间点（>1小时）突出。尽管LPS诱导的初始I κ B-α降解受β-激动剂的影响最小，但后者在随后的时间点（>1 h）诱导胞质I κ B-α水平显著反弹，并伴有I κ B-α胞质半衰期增加。这可能解释了所观察到的细胞质隔室中的核因子-κ B隔离。我们推测β-受体激动剂的抗炎作用在于其增加I κ B-α细胞质浓度的能力，可能是通过减少其降解。
In addition to their well-studied bronchodilatory and cardiotonic effects, beta-adrenergic agonists carry anti-inflammatory properties by inhibiting cytokine production by human mononuclear cells. In a model of human promonocytic THP-1 cells stimulated with lipopolysaccharide (LPS), we showed that beta-agonists inhibited tumor necrosis factor-alpha and interleukin-8 production predominantly via the beta(2)-adrenergic receptor through the generation of cAMP and activation of protein kinase A. This effect was reproduced by other cAMP-elevating agents such as prostaglandins and cAMP analogs. Activation and nuclear translocation of the transcription factor nuclear factor-kappa B induced by LPS were inhibited with treatment with beta-agonists, an effect that was prominent at late time points (>1 h). Although the initial I kappa B-alpha degradation induced by LPS was minimally affected by beta-agonists, the latter induced a marked rebound of the cytosolic I kappa B-alpha levels at later time points (>1 h), accompanied by an increased I kappa B-alpha cytoplasmic half-life. This potentially accounts for the observed nuclear factor-kappa B sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of beta-agonists reside in their capacity to increase cytoplasmic concentrations of I kappa B-alpha, possibly by decreasing its degradation.