Portland Veterans Affairs Medical Center, Portland, Oregon, United States of America.
PLoS One. 2010 Sep 28;5(9):e13058. doi: 10.1371/journal.pone.0013058.
Abnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer's disease and multiple sclerosis (MS). Lipoic acid (LA) has been shown to have antioxidant and anti-inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production via activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects.
METHODOLOGY/PRINCIPAL FINDINGS: We determined the effects of LA on IL-6, IL-17 and IL-10 secretion using ELISAs. Treatment with 50 µg/ml and 100 µg/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline.
CONCLUSIONS/SIGNIFICANCE: Oral administration of LA in vivo resulted in significant increases in cAMP concentration. The anti-inflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA.
炎症反应的异常调节是糖尿病、阿尔茨海默病和多发性硬化症（MS）等疾病的重要组成部分。硫辛酸（LA）具有抗氧化和抗炎特性，目前正在被研究作为这些疾病的治疗方法。我们首先报道 LA 通过激活 G 蛋白偶联受体和腺苷酸环化酶来刺激 cAMP 的产生。LA 还抑制 NK 细胞的激活和细胞毒性。在这项研究中，我们提供了支持 LA 的抗炎特性是通过 cAMP/PKA 信号级联介导的假设的证据。此外，我们还表明，LA 口服给药可提高 MS 患者的 cAMP 水平。
方法/主要发现：我们使用 ELISA 法确定 LA 对 IL-6、IL-17 和 IL-10 分泌的影响。用 50µg/ml 和 100µg/ml 的 LA 处理可使 T 细胞富集的 PBMCs 中的 IL-6 水平分别降低 19%和 34%。IL-17 水平也分别降低了 35%和 50%。虽然没有统计学意义，但 LA 似乎对 IL-10 的产生有双相作用。胸苷掺入研究表明，LA 抑制 T 细胞增殖 90%。通过 IL-2 分泌测量，T 细胞的激活减少了 50%。Western blot 分析表明，LA 处理增加了蛋白激酶 A 的下游效应物 Lck 的磷酸化。用 PKA 的肽抑制剂 PKI 预处理可阻断 LA 对 IL-2 和 IFNγ产生的抑制作用，表明 PKA 介导了这些反应。LA 口服给予 MS 患者 1200mg，摄入后 4 小时 PBMC 中的 cAMP 水平升高。20 名受试者的平均 cAMP 水平比基线高 43%。
结论/意义：LA 在体内的口服给予导致 cAMP 浓度的显著增加。LA 的抗炎作用部分是通过 cAMP/PKA 信号级联介导的。这些新发现增强了我们对 LA 作用机制的理解。
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