Mechanisms underlying the inhibitory actions of the pentacyclic triterpene α-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate
Mechanisms underlying the inhibitory actions of the pentacyclic triterpene α-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate
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DOI：
10.1016/j.ejphar.2006.12.005
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发表时间：
2007-03-22
影响因子：
5
通讯作者：
Calixto, Joao B.
中科院分区：
文献类型：
--
作者：
Medeiros, Rodrigo;Otuki, Michel F.;Calixto, Joao B.
本研究评价了α-香树脂醇（一种从Protium Kleinii和其他植物中分离的五环三萜）对12-O-十四烷酰基佛波醇乙酸酯（TPA）诱导的小鼠皮肤炎症发挥作用的一些机制。局部应用α-香树脂醇（0.1-1 mg/耳）剂量依赖性地抑制TPA诱导的前列腺素E-2（PGE（2））水平的增加。与选择性环氧合酶（考克斯）-1 SC 560 [5-（4-氯苯基）-1-（4-甲氧基苯基）-3-三氟甲基吡唑]或考克斯-2罗非昔布抑制剂相比，α-阿米芬在体外不能改变考克斯-1或考克斯-2活性。Western印迹分析显示，α-香树脂蛋白剂量依赖性地抑制TPA诱导的小鼠皮肤中的考克斯-2表达。对核因子-κ B（NF-κ B）通路的评价显示，用α-香树脂蛋白局部处理能够防止I κ B α降解、p65/RelA磷酸化和NF-κ B活化。此外，局部给予的α-香树素剂量依赖性地抑制上游蛋白激酶的活化，即在局部TPA治疗后的细胞外信号调节蛋白激酶（ERK）、p38促分裂原活化蛋白激酶（MAPK）和蛋白激酶C（PKC）α。总的来说，目前的结果表明，局部皮肤应用α-香树脂蛋白发挥TPA诱导的炎症的强烈和快速的抑制作用。这些作用似乎与皮肤PGE（2）水平的抑制有关，其机制包括通过抑制上游蛋白激酶（即ERK、p38 MAPK和PKC α）和阻断NF-κ B活化来抑制考克斯-2表达。这些结果表明α-香树脂醇衍生物可能与开发用于管理炎性疾病的局部药剂潜在相关。(c)2006 Elsevier B. V.保留所有权利。
The present study evaluated some of the mechanisms through which alpha-amyrin, a pentacyclic triterpene isolated from Protium Kleinii and other plants, exerts its effects against 12-O-tetradecanoylphorbol-acetate (TPA)-induced skin inflammation in mice. Topical application of a-amyrin (0.1-1 mg/ear) dose-dependently inhibited TPA-induced increase of prostaglandin E-2 (PGE(2)) levels. In contrast with the selective cyclooxygenase (COX)-1 SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or COX-2 rofecoxib inhibitors, alpha-amyfin failed to alter either COX-1 or COX-2 activities in vitro. Western blot analysis revealed that a-amyrin dose-dependently inhibited TPA-induced COX-2 expression in the mouse skin. The evaluation of nuclear factor-kappa B (NF-kappa B) pathway revealed that topical treatment with alpha-amyrin is able to prevent I kappa B alpha degradation, p65/RelA phosphorylation and NF-kappa B activation. Moreover, alpha-amyrin given topically dose-dependently inhibited the activation of upstream protein kinases, namely extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC)alpha, following topical TPA treatment. Collectively, present results suggest that topical skin application of alpha-amyrin exerts a strong and rapid onset inhibition of TPA-induced inflammation. These effects seem to be associated with the suppression of skin PGE(2) levels by mechanisms involving the suppression of COX-2 expression, via inhibition of upstream protein kinases - namely ERK, p38 MAPK and PKC alpha - and blocking of NF-kappa B activation. These results indicate that a-amyrin-derivative could be potentially relevant for the development of a topical agent for the management of inflammatory diseases. (c) 2006 Elsevier B.V. All rights reserved.