School of Medical Sciences, University of Aberdeen, AB25 2ZD, UK.
J Neuroinflammation. 2011 Feb 4;8:10. doi: 10.1186/1742-2094-8-10.
The neuropeptide substance-P (SP) is expressed from the TAC1 gene in sensory neurones where it acts as a key modulator of neurogenic inflammation. The promoter of TAC1 (TAC1prom) plays a central role in the regulation of the TAC1 gene but requires the presence of a second regulatory element; ECR2, to support TAC1 expression in sensory neurones and to respond appropriately to signalling pathways such as MAPkinases and noxious induction by capsaicin. We examined whether the effect of capsaicin on ECR2-TAC1prom activity in larger diameter neurones was cell autonomous or non- cell autonomous. We demonstrate that TRPV1 is not expressed in all the same cells as SP following capsaicin induction suggesting the presence of a non-cell autonomous mechanism for TAC1 up-regulation following capsaicin induction. In addition, we demonstrate that induction of SP and ECR1-TAC1prom activity in these larger diameter neurones can be induced by potassium depolarisation suggesting that, in addition to capsaicin induction, transgene activity may be modulated by voltage gated calcium channels. Furthermore, we show that NK1 is expressed in all SP- expressing cells after capsaicin induction and that an agonist of NK1 can activate both SP and the transgene in larger diameter neurones. These observations suggest the presence of an autocrine loop that controls the expression of the TAC1 promoter in sensory neurones. In contrast, induction of the TAC1 promoter by LPS was not dependent on ECR2 and did not occur in large diameter neurones. These studies demonstrate the diversity of mechanisms modulating the activity of the TAC1 promoter and provide novel directions for the development of new anti-inflammatory therapies.
神经肽物质 P（SP）由感觉神经元中的 TAC1 基因表达，作为神经源性炎症的关键调节剂。TAC1（TAC1prom）的启动子在 TAC1 基因的调节中起着核心作用，但需要第二个调节元件 ECR2 的存在，以支持感觉神经元中 TAC1 的表达，并对 MAPkinases 等信号通路和辣椒素引起的有害诱导做出适当反应。我们研究了辣椒素对大直径神经元中 ECR2-TAC1prom 活性的影响是否具有细胞自主性或非细胞自主性。我们证明，在辣椒素诱导后， TRPV1 并非在所有与 SP 相同的细胞中表达，这表明在辣椒素诱导后 TAC1 的上调存在非细胞自主机制。此外，我们证明，钾去极化可以诱导这些大直径神经元中 SP 和 ECR1-TAC1prom 活性的诱导，这表明除了辣椒素诱导外，转基因活性可能还受到电压门控钙通道的调节。此外，我们还表明，在辣椒素诱导后，所有表达 SP 的细胞中都表达了 NK1，并且 NK1 的激动剂可以激活大直径神经元中的 SP 和转基因。这些观察结果表明存在一种自分泌环，控制感觉神经元中 TAC1 启动子的表达。相比之下，LPS 诱导 TAC1 启动子的作用不依赖于 ECR2，也不会发生在大直径神经元中。这些研究表明了调节 TAC1 启动子活性的多种机制，并为开发新的抗炎治疗方法提供了新的方向。
