Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China.
Acta Biochim Biophys Sin (Shanghai). 2011 Jan;43(1):61-8. doi: 10.1093/abbs/gmq109. Epub 2010 Dec 3.
α-Melanocyte-stimulating hormone (α-MSH), an anti-inflammatory and immunomodulatory neuropeptide, has been shown to be effective in the experimental treatment of autoimmune diseases and allograft rejection. However, its regulatory mechanism is still unclear. Mature dendritic cells (DCs) are pivotal initiators of immune response and inflammation. We hypothesized that the regulatory role of α-MSH in DC maturation would contribute to the effects of α-MSH in immune-response-mediated disease models. It was found that α-MSH inhibited tumor necrosis factor-alpha (TNF-α)-induced maturation of human peripheral-monocyte-derived DCs (MoDCs), both phenotypically and functionally. This occurred through the down-regulation of the expression of co-stimulatory molecules CD83 and CD86, the production of IL-12, the promotion of IL-10 secretion, and the MoDC phagocytic activity, suggesting that the inhibition of DC maturation by α-MSH could contribute to the anti-inflammatory effect of this neuropeptide. Furthermore, increased expression of annexin A1 (ANXA1) was found to be responsible for the α-MSH inhibiting effect on TNF-α-induced MoDC maturation, which could be abolished by the treatment of MoDCs with specific, small interfering RNAs targeting ANXA1 (ANXA1-siRNA), suggesting that α-MSH-induced ANXA1 mediates the inhibition. Therefore, α-MSH inhibits TNF-α-induced maturation of human DCs through α-MSH-up-regulated ANXA1, suggesting that inhibition of the maturation of DCs by α-MSH could mediate the anti-inflammatory effect of the neuropeptide. Furthermore, ANXA1 could be identified as a new therapeutic drug target based on the role of DCs in immune-mediated inflammatory diseases.
α-促黑素细胞激素（α-MSH）是一种具有抗炎和免疫调节作用的神经肽，已被证明在治疗自身免疫性疾病和同种异体移植物排斥反应的实验中有效。然而，其调节机制尚不清楚。成熟树突状细胞（DCs）是免疫反应和炎症的关键启动者。我们假设 α-MSH 对 DC 成熟的调节作用将有助于 α-MSH 在免疫反应介导的疾病模型中的作用。研究发现，α-MSH 抑制肿瘤坏死因子-α（TNF-α）诱导的人外周单核细胞来源的 DC（MoDC）的成熟，无论是表型还是功能。这是通过下调共刺激分子 CD83 和 CD86 的表达、IL-12 的产生、促进 IL-10 分泌以及 MoDC 的吞噬活性来实现的，这表明 α-MSH 对 DC 成熟的抑制作用可能有助于这种神经肽的抗炎作用。此外，发现 Annexin A1（ANXA1）的表达增加是导致 α-MSH 抑制 TNF-α诱导的 MoDC 成熟的原因，用针对 ANXA1 的特异性小干扰 RNA（ANXA1-siRNA）处理 MoDC 可以消除这种抑制作用，这表明 α-MSH 诱导的 ANXA1 介导了这种抑制作用。因此，α-MSH 通过 α-MSH 上调的 ANXA1 抑制 TNF-α诱导的人 DC 成熟，这表明 α-MSH 抑制 DC 成熟可介导神经肽的抗炎作用。此外，基于 DC 在免疫介导的炎症性疾病中的作用，ANXA1 可被确定为一种新的治疗药物靶标。
