α-melanocyte-stimulating hormone down-regulates CXC receptors through activation of neutrophil elastase
α-melanocyte-stimulating hormone down-regulates CXC receptors through activation of neutrophil elastase
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DOI：
10.1002/eji.200535209
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Sreenivasan, Y
中科院分区：
文献类型：
--
作者：
Manna, SX;Sarkar, A;Sreenivasan, Y
考虑到白细胞介素-8（IL-8）在大量急性和慢性炎性疾病中的作用，IL-8介导的生物学应答的调节是重要的。α-促黑素细胞激素（α-MSH）是一种十三肽，通过一种未知的机制抑制大多数形式的炎症。在本研究中，我们发现α-MSH主要与黑皮质素-1受体相互作用，并抑制巨噬细胞和中性粒细胞中的几种IL-8诱导的生物反应。它下调了中性粒细胞中IL-8的受体，但不下调TNF、IL-4、IL-13或TNF相关凋亡诱导配体（TRAIL）的受体。它下调CXCR 1和2型，但不下调mRNA水平。α-MSH不抑制纯化的细胞膜或亲和纯化的CXCR中的IL-8结合。IL-8或抗CXCR Ab保护免受α-MSH介导的IL-8结合抑制。中性粒细胞弹性蛋白酶，一种特异性丝氨酸蛋白酶，但不是组织蛋白酶G或蛋白酶3的水平增加在α-MSH处理的细胞，和CXCR的恢复由特定的中性粒细胞弹性蛋白酶或丝氨酸蛋白酶抑制剂表明弹性蛋白酶参与α-MSH诱导的下调CXCR。这些研究表明，α-MSH通过诱导丝氨酸蛋白酶下调CXCR来抑制IL-8介导的生物反应，并且α-MSH在嗜中性粒细胞驱动的炎症性窘迫中充当有效的免疫调节剂。
Considering the role of interleukin-8 (IL-8) in a large number of acute and chronic inflammatory diseases, the regulation of IL-8-mediated biological responses is important. Alpha-melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide, inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that alpha-MSH interacts predominantly with melanocortin-1 receptors and inhibits several IL-8-induced biological responses in macrophages and neutrophils. it downregulated receptors for IL-8 but not for TNF, IL-4, IL-13 or TNF-related apoptosis-inducing ligand (TRAIL) in neutrophils. It down-regulated CXCR type 1 and 2 but not mRNA levels. a-MSH did not inhibit IL-8 binding in purified cell membrane or affinity-purified CXCR. IL-8 or anti-CXCR Ab protected against alpha-MSH-mediated inhibition of IL-8 binding. The level of neutrophil elastase, a specific serine protease, but not cathepsin G or proteinase 3 increased in alpha-MSH-treated cells, and restoration of CXCR by specific neutrophil elastase or serine protease inhibitors indicates the involvement of elastase in alpha-MSH-induced down-regulation of CXCR. These studies suggest that alpha-MSH inhibits IL-8-mediated biological responses by down-regulating CXCR through induction of serine protease and that alpha-MSH acts as a potent immunomodulator in neutrophil-driven inflammatory distress.