Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo.
Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo.
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DOI：
10.1371/journal.pone.0075426
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nichols CD
中科院分区：
文献类型：
--
作者：
Nau F Jr;Yu B;Martin D;Nichols CD
肿瘤坏死因子α (TNF-α)在炎症中起关键作用，其产生和信号传导参与许多炎症相关疾病。最近，我们发现激动剂(R)-DOI选择性激活5-羟色胺5-HT2A受体，对大鼠原发主动脉平滑肌细胞的促炎标志物产生超强阻断作用。在这里，我们证明了(R)-DOI的全身管理可以阻断TNF-α在整个动物的全身作用，在主动脉弓和小肠具有强大的抗炎作用。这包括阻断TNF-α-诱导的促炎细胞粘附（Icam-1、Vcam-1）、细胞因子（Il-6、IL-1b）和趋化因子（Mcp-1、Cx3cl1）基因的表达，以及肠中Vcam-1蛋白的表达。此外，系统性(R)-DOI还能阻止TNF-α-诱导的循环IL-6升高。重要的是，利用受体选择性拮抗剂，我们已经证明(R)-DOI全身抗炎作用的机制是激活5-HT2A受体。我们的研究结果强调了5-HT2A受体在炎症过程中的强大新作用，并表明5-羟色胺受体的激动作用可能代表了一种有效的新方法，可以开发有效的小分子治疗炎症性疾病和病症，如动脉粥样硬化和炎症性肠病。
Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.
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